A Tailored Thermosensitive PLGA-PEG-PLGA/Emulsomes Composite for Enhanced Oxcarbazepine Brain Delivery via the Nasal Route

Abstract

The use of nanocarrier delivery systems for direct nose to brain drug delivery shows promise for achieving increased brain drug levels as compared to simple solution systems. An example of such nanocarriers is emulsomes formed from lipid cores surrounded and stabilised by a corona of phospholipids (PC) and a coating of Tween 80, which combines the properties of both liposomes and emulsions. Oxcarbazepine (OX), an antiepileptic drug, was entrapped in emulsomes and then localized in a poly(lactic acid-co-glycolic acid)-poly(ethylene glycol)-poly(lactic acid-co-glycolic acid) (PLGA-PEG-PLGA) triblock copolymer thermogel. The incorporation of OX emulsomes in thermogels retarded drug release and increased its residence time (MRT) in rats. The OX-emulsome and the OX-emulsome-thermogel formulations showed in vitro sustained drug release of 81.1 and 53.5%, respectively, over a period of 24 h. The pharmacokinetic studies in rats showed transport of OX to the systemic circulation after nasal administration with a higher uptake in the brain tissue in case of OX-emulsomes and highest MRT for OX-emulsomal-thermogels as compared to the IN OX-emulsomes, OX-solution and Trileptal^® suspension. Histopathological examination of nasal tissues showed a mild vascular congestion and moderate inflammatory changes around congested vessels compared to saline control, but lower toxic effect than that reported in case of the drug solution.

Keywords: antiepileptic drug; block copolymers; drug delivery; nose to brain delivery; thermogel system.

Figure 1

Schematic diagram of the sol-gel transition of BAB type poly(lactic acid-co-glycolic acid)-poly(ethylene glycol)-poly(lactic acid-co-glycolic acid) (PLGA-PEG-PLGA) tri-block copolymer aqueous solution in response to temperature.

Figure 2

(A,B) are the photographs of a PLGA-PEG-PLGA copolymer solution prior to sol-gel transition (A) and formation of opaque solution (B), thermogels produced after sol-gel transition retain their position (C). (D) is the phase diagrams of polymers prepared from different PLGA-PEG-PLGA copolymer concentrations with different emulsomes loading, showing sol-gel and gel-precipitate transitions).

Figure 3

Rheograms of thermogels G3, G7, G11 and G15 prepared from 20% w/w PLGA-PEG-PLGA copolymer solution (A) and thermogels G4, G8, G12 and G16 prepared from 30% w/w PLGA-PEG-PLGA copolymer solution (B) in combination with 0, 10, 25, and 50% v/v emulsomes measured at 37 °C.

Figure 4

Release profiles of Oxcarbazepine (OX) from emulsomes and G16 emulsomal thermogel.

Figure 5

Mean OX concentrations in plasma (A) in brain (B) of rat groups receiving IN administration of emulsomes, G16 emulsomal thermogel, OX solution and Oral Trileptal^® suspension. Data of IN administration of emulsomes, and Oral Trileptal^® suspension reproduced with permission from El-Zaafarany et al. [40], Elsevier, 2016.

Figure 6

Light micrograph of (A) untreated nasal rat epithelium (with saline only) showing normal structure of the nose (no) with intact mucosal epithelium (mu). (B) nasal rat epithelium treated with OX-loaded G16 emulsomal thermogel showing intact mucosal epithelium (mu) with minimal focal inflammatory cells infiltration (m). (Maginifcation 16×).