Lamellar
liposome technology has been used for several decades to produce sustained-release drug formulations for parenteral administration. Multivesicular
liposomes are structurally distinct from lamellar
liposomes and consist of an aggregation of hundreds of water-filled polyhedral compartments separated by bi-layered
lipid septa. The unique architecture of multivesicular
liposomes allows encapsulating
drug with greater efficiency, provides robust structural stability and ensures reliable, steady and prolonged drug release. The favourable characteristics of multivesicular
liposomes have resulted in many
drug formulations exploiting this technology, which is proprietary and referred to as DepoFoam. Currently, two formulations using multivesicular
liposome technology are approved by the US FDA for clinical use, and many more formulations are at an experimental developmental stage. The first clinically available formulation contains the
antineoplastic agent cytarabine (DepoCyt) for its
intrathecal injection in the treatment of malignant lymphomatous
meningitis.
Intrathecal injection of DepoCyt reliably results in the sustained release of
cytarabine and produces cytotoxic concentrations in cerebrospinal fluid (CSF) that are maintained for at least 2 weeks. Early efficacy data suggest that DepoCyt is fairly well tolerated, and its use allows reduced dosing frequency from twice a week to once every other week and may improve the outcome compared with frequent
intrathecal injections of unencapsulated
cytarabine. The second available formulation contains
morphine (DepoDur) for its single
epidural injection in the treatment of
postoperative pain. While animal studies confirm that
epidural injection of DepoDur results in the sustained release of
morphine into CSF, the CSF pharmacokinetics have not been determined in humans. Clinical studies suggest that the use of DepoDur decreases the amount of systemically administered
analgesics needed for adequate
postoperative pain control. It may also provide superior
pain control during the first 1-2 postoperative days compared with epidural administration of unencapsulated
morphine or
intravenous administration of an
opioid. However, at this timepoint the overall clinical utility of DepoDur has yet to be defined and some safety concerns remain because of the unknown CSF pharmacokinetics of DepoDur in humans. The versatility of multivesicular
liposome technology is reflected by the many agents including small inorganic and organic molecules and macromolecules including
proteins that have successfully been encapsulated. Data concerning many experimental formulations containing
antineoplastic, antibacterial and
antiviral agents underscore the sustained, steady and reliable release of these compounds from multivesicular
liposomes after injection by the intrathecal, subcutaneous, intramuscular, intraperitoneal and intraocular routes. Contingent on the specific formulation and manufacturing process, agents were released over a period of hours to weeks as reflected by a 2- to 400-fold increase in elimination half life. Published data further suggest that the encapsulation process preserves bioactivity of agents as delicate as
proteins and supports the view that examined multivesicular
liposomes were non-toxic at studied doses. The task ahead will be to examine whether the beneficial structural and pharmacokinetic properties of multivesicular
liposome formulations will translate into improved clinical outcomes, either because of decreased
drug toxicity or increased
drug efficacy.