A Review on Multivesicular Liposomes (MVLs) Application in Controlled Drug Delivery

Several challenges, including rapid drug release from the carrier, repeated drug administration, fluctuations in plasma drug concentration, and reduced patient compliance have been reported for conventional drug delivery systems. Liposomes were first developed by a scientist, A.D. Bangham, in 1961. The word liposome is a combination of the two Greek words “lipos” meaning fat and “soma” meaning body. A liposome is a system, which its membrane is made up of fatty compounds such as lipids. The lipid membrane and its entrapped space are suitable for the loading of lipophilic and hydrophilic drug molecules, respectively. Liposomes, as optimal drug delivery systems, could be an appropriate solution to many of the challenges of conventional drug delivery systems.    Liposomes, which are made from phospholipid and cholesterol, have many benefits as optimal drug delivery systems. A wide range of therapeutics could be incorporated within liposomal carriers. They are biodegradable and biocompatible. They do not stimulate the immune system and are used as a synthetic membrane model. These systems increase the stability of drugs in the body by protecting the drug compounds within them and also reduce the toxic effects of drugs by minimizing drug exposure to sensitive tissues. Liposomes can also control drug release.    The particle size of liposomes varies from nanometers to micrometers depending on the preparation method. Liposomes can be classified on the basis of their size and bilayers number, into: giant unilamellar vesicles (GUVs) 0.5 – 10 µm;  multilamellar vesicles (MLV) 1 - 5 µm; large unilamellar vesicles (LUV) around 100 – 500 nm; small unilamellar vesicles (SUV) 20 - 100 nm; and multivesicular liposomes (MVL). MVL are characterized by their structure of multiple non-concentric aqueous chambers surrounded by a network of lipoidal membranes. The particle size of monolayer and multilayer liposomes is about a few hundred nanometers, while the average particle size of MVLs is 1 to 100 µm.    Methods of liposomes preparation include thin layer hydration, reverse phase evaporation, solvent injection, dehydration-rehydration, and ultrasonic. The MVL system is a water in oil in water emulsion (W / O / W) that organic phase contains hydrophobic material and liquid phase contains hydrophilic material. The double emulsification method is the most common method of MVL preparation.
Small drugs as well as large molecules such as peptides and proteins can be loaded in the unique structure of MVL. So far, several peptides or protein compounds have been successfully loaded in MVL and their therapeutic effects investigated in various diseases. In vitro and in vivo studies show that MVLs well control the drug release rate. There are some examples for MVL applications regarding these compounds.; MVL containing insulin or liraglutide in diabetes mellitus treatment, bevacizumab in laser-induced choroidal neovascularization, thymopentin in immune disorders, LXT-101 in the treatment of prostate cancer, angiotensin I converting enzyme (ACE) inhibitory peptide in the treatment of hypertension, alfa interferon in hepatitis C, and leridistim in chemotherapy-induced bone marrow suppression are some of the studies in this field.
    
   MVL consists of four compounds: phospholipids, cholesterol, neutral triglycerides, and negatively charged lipids. Phospholipid chains form the bilayer membrane of the liposome, and the cholesterol in the system is located between these chains. The cholesterol to phospholipids ratio, lipid to drug ratio, and lipidic composition affect the stability of the system and the rate of drug release. Neutral triglycerides such as triolein, tricaprylene, trilaureine and tributyrine allow the formation of this unique multivesicular structure, stabilize the membranes of internal vesicles at the point of contact with each other, preventing them from merging and controlling the drug release rate. Negatively charged lipids such as dicetyl phosphate (DCP) also control particle accumulation by inducing a negative charge on the surface of liposomes.
Observation and determination of MVL structure are usually performed by optical and electron microscopes. The sysyems should also be characterized regarding drug encapsulation, drug release profile and kinetics, storage stability, and drug-vesicle interaction.  Most studies on the MVL drug delivery system have been performed on drug-loaded MVLs. To date, application of MVLs containing tramadol in pain management, various compounds (include rose bengal, oxaliplatin, oleanolic acid, and cytarabine) in cancer, dexamethasone sodium phosphate in hearing impairment, acyclovir sodium in infectious diseases of herpes simplex virus (HSV), desferrioxamine mesylate in iron toxicity, celecoxib as an anti-inflammatory and analgesic agent, breviscapine in cardiovascular disease and cerebrovascular ischemia, flucinolone acetonide in ocular inflammatory diseases, naltrexone hydrochloride in opioid abuse and alcohol dependence and ropivacaine hydrochloride in local anesthesia has been investigated.  
In some treatment protocols, the simultaneous administration of two-drug combinations is required to achieve the desired result. The large aqueous space in the MVL and the division of this space into intravesicular and extra-vesicular parts, allows multiple drug combinations to be loaded in it and enter the body during an administration. The efficacy of co-delivery of mitoxantrone hydrochloride with horseradish peroxidase and insulin with metformin in a system was investigated in the treatment of cancer and diabetes mellitus, respectively, and showed satisfactory effects. Another class of drugs that have been successfully loaded in MVL is antibiotics. Antibiotics should have the least fluctuations in plasma concentrations in order to be more effective on microorganisms, so they should be prescribed according to a regular schedule. In MVL studies, researchers found satisfactory results from the study of the two antibiotics vancomycin and gentamicin.   
Many liposomal systems are used clinically to control drug release. These systems include daunorubicin, desferrioxamine mesylate, insulin-like growth factor 1 (IGF-1), doxorubicin, vincristine sulfate, and irinotecan respectively under the brand names DaunoXome®, DepoDFO®, DepoIGF-I®, Doxil®, Marqibo®, and Onivyde®. Depofoam is a type of MVL system with a particle size of 10 to 20 µm that could be a good depot in the body and releases the drug in a controlled manner. Depofoams are good choices for drug delivery to tumor areas and sensitive areas of the body such as the eyes, spinal cord, and epidural, and can reduce drug toxicity and side effects by minimizing drug exposure to healthy parts of the body.    There are several Depofoam systems which three of these systems have been approved by the US Food and Drug Administration (FDA). DepoCyt® is a Depofoam system of the anticancer drug cytarabine by intrathecal injection. This system releases the drug in the body for two weeks and makes an optimum concentration of it in the cerebrospinal fluid (CSF). DepoDur® is the second product, which contains morphine. It relieves post-surgery pain after epidural administration and reduces the use of other injectable analgesics. Exparel® is a new formulation of bupivacaine with an analgesic effect that is injected near the surgical site. Numerous animal and human studies showed that after intrathecal, epidural, intraocular, intramuscular, intravenous, intra-arterial, and subcutaneous administration of Depofoam.
This review article provides an overview of recent studies on the MVL system and its effect on optimizing rate of drug release. Successful loading of large molecules such as proteins and the possibility of loading multiple drug combinations into one system shows a hopeful view for the future of MVL in the pharmaceutical industry. It seems that this new technology, by overcoming the problems caused by frequent drug administration, has created an additional incentive for researchers to advance in this field. However, problems such as the high cost of these liposomes are some of the challenges that they face.