Evaluation of the physical properties and stability of two lipid drug delivery systems containing mefloquine

Abstract

Stability data is used to determine the change the product has undergone over a certain time period at specific temperatures. In the present study, the physical stability characterized by size, pH and entrapment efficacy of mefloquine loaded liposomes and Pheroid™ vesicles were investigated. Size was accurately determined by flow cytometry. Entrapment efficacy, after unentrapped drug was removed was successfully determined by UV-spectrophotometry. The formulations contained 0.5% (m/v) mefloquine and results showed that mefloquine interfered with the formation of lipid bilayer of the liposomes. Liposomes increased in size from 5.22 ± 0.03 μm to 9.71 ± 1.11 μm with accelerated stability and large aggregates were observed. A notable difference in stability testing of Pheroid™ vesicles was seen with no significant increase in size. Entrapment efficacy of 68.72 ± 0.04% (5 °C), 67.45 ± 2.92% (25 °C) and 67.45 ± 2.92% (30 °C) were obtained at the different storage conditions. With these findings the mefloquine loaded Pheroid™ vesicles are stable and should be used investigated for the possible increase in efficacy and bioavailability and decrease toxicity.

Introduction

Due to an increase in demand for more effective and safer drugs, drug delivery systems development has increased in the last decades (Buszello and Müller, 2000, Ranade and Hollinger, 2004). These systems can transport drugs for site specific delivery leading to enhanced efficacy and bioavailability, decrease adverse reactions and improve patient compliance (Date et al., 2007, Mahato, 2007, Ranade and Hollinger, 2004). Colloidal drug carriers consist of a dispersed phase in a continuous phase and have been investigated for targeted delivery (Buszello and Müller, 2000, Date et al., 2007, Mahato, 2007).

The most extensively researched colloidal system is liposomes (Sharma and Sharma, 1997). The vesicles are composed of a lipid bilayer with an aqueous compartment (New, 1990, Sharma and Sharma, 1997) and can entrap both hydrophilic and lipophilic drugs increasing the versatility of liposomes (Date et al., 2007, New, 1990). Liposome properties vary considerably with lipid composition, size and method of preparation (Betageri et al., 1993). Liposomes differ in size from 80 nm to 100 μm and can be manipulated according to specific requirements (New, 1990, Sharma and Sharma, 1997). Site specific delivery, sustained release and reduction in toxicity are some of the advantages of this lipid drug delivery system (Betageri et al., 1993, Date et al., 2007, New, 1990). Research into the application of liposomes in malaria include artemether (Joshi et al., 2008a, Joshi et al., 2008b), artesunate (Gabriels and Plaizier-Vercammen, 2003), chloroquine (Qiu et al., 2008) and primaquine (Stensrud et al., 2000).

Pheroid™ technology is a patented colloidal delivery system consisting of a dispersed phase of plant and essential fatty acid in a nitrous oxide saturated continuous water phase. Pheroid™ also consists of a lipid bilayer that is dynamic and constantly changing, but has high stability. Like liposomes, Pheroid™ can entrap both hydrophilic and lipophilic drugs. Pheroid™ lipid carrier system can be manipulated in formulation, structure and size for various applications (Grobler et al., 2007). Pheroid™ has been successfully used in nasal peptide delivery (Du Plessis et al., 2010), transdermaly (Gerber et al., 2008, Grobler et al., 2007, Saunders et al., 1999) and cosmetic application (Grobler et al., 2007).

Malaria affects billions of people in 109 countries worldwide, almost half situated in Africa (WHO, 2010a, WHO, 2010b)(WHO, 2010a, WHO, 2010c). Malaria is responsible for 20% of deaths in children (WHO, 2010b). Anti-parasitic disease drug discovery only accounts for 1% of new drug development (Date et al., 2007). Mefloquine, a blood schizonticidal drug, is used as treatment and chemoprophylaxis of malaria (Basco, 2007, Rosenthal, 2004). Mefloquine in combination with artemisinins showed to be highly effective with good tolerability (Bouyou-Akotet et al., 2010, Congpuong et al., 2010). Adverse reactions include gastrointestinal and neurological disturbances (Rosenthal, 2004). Neurotoxicity has been demonstrated in vitro (Dow et al., 2003), in vivo (Dow et al., 2006) and numerous reports of neurological symptoms in humans exist (Arguin and Steele, 2010, Rendi-Wagner et al., 2002). Mefloquine has been successfully formulated in emulsions with satisfactory stability and high antimalarial activity (Mbela et al., 1998, Mbela et al., 1994). Stability is mainly evaluated to ensure the product will remain in a state of adequate quality throughout its shelf life and is most difficult to attain (Rhodes, 1979). Stability testing under different environmental factors provides evidence of the quality of the product needed for registration (ICH, 2006).

These lipid based colloidal drug delivery systems is similar in structure, size and drug loading ability. The present study is intended to evaluate the physical stability of mefloquine loaded Pheroid™ vesicles and liposomes under different storage condition for three months. Characteristics under investigation include the flow cytometric evaluation of size, entrapment efficacy by means of UV-spectrophotometry and pH.