Formulation and in Vitro, ex Vivo and in Vivo Evaluation of Elastic Liposomes for Transdermal Delivery of Ketorolac Tromethamine

Abstract

The objective of the current study was to formulate ketorolac tromethamine-loaded elastic liposomes and evaluate their in vitro drug release and their ex vivo and in vivo transdermal delivery. Ketorolac tromethamine (KT), which is a potent analgesic, was formulated in elastic liposomes using Tween 80 as an edge activator. The elastic vesicles were prepared by film hydration after optimizing the sonication time and number of extrusions. The vesicles exhibited an entrapment efficiency of 73 ± 11%, vesicle size of 127.8 ± 3.4 nm and a zeta potential of −12 mV. In vitro drug release was analyzed from liposomes and an aqueous solution, using Franz diffusion cells and a cellophane dialysis membrane with molecular weight cut-off of 8000 Da. Ex vivo permeation of KT across pig ear skin was studied using a Franz diffusion cell, with phosphate buffer (pH 7.4) at 32 °C as receptor solution. An in vivo drug permeation study was conducted on healthy human volunteers using a tape-stripping technique. The in vitro results showed (i) a delayed release when KT was included in elastic liposomes, compared to an aqueous solution of the drug; (ii) a flux of 0.278 μg/cm2h and a lag time of about 10 h for ex vivo permeation studies, which may indicate that KT remains in the skin (with the possibility of exerting a local effect) before reaching the receptor medium; (iii) a good correlation between the total amount permeated, the penetration distance (both determined by tape stripping) and transepidermal water loss (TEWL) measured during the in vivo permeation studies. Elastic liposomes have the potential to transport the drug through the skin, keep their size and drug charge, and release the drug into deep skin layers. Therefore, elastic liposomes hold promise for the effective topical delivery of KT.

Untitled

“…The obtained results (Table 1) demonstrated that, by using PL90G, PL80H and PL90H the EE were found approximately 86.67, 74.58 and 80.62% at 1:1 ratio of CH: PL. The results were consistent with previous published reports 36 . Thus, it can be concluded that, stoichio-metric ratio between cholesterol and phospholipids, in addition to selection of proper phospholipids with highest phosphatidylcholine content might be responsible for obtaining highest EE.…”

Investigation of Effect of Phospholipids on Physical and Functional Characterization of Paclitaxel Liposomes

“…highest incorporation of PT in liposomal vesicles was found to be enhanced by increasing the ratios between CH and phospholipids, but then declined suddenly as further increasing the ratio. The results were consistent with previously published reports [37]. Thus, it can be concluded that a stoichiometric ratio between CH and phospholipids, in addition to the selection of proper phospholipids with highest phosphatidylcholine content, might be responsible for obtaining highest EE.…”

Elastic liposomes as novel carriers: recent advances in drug delivery

“…82,83 A good correlation between the permeation flux (permeation flux of 0.278 µg/cm 2 /h) and TEWL was found. 83 Another report studied ketorolac interactions (chemical stability) with the lipid bilayer of ELs using double-chain (sucrose laurate ester) and single-chain surfactants (octaoxyethylenelaurate ester). 84 Hydrophilic diclofenac sodium has been delivered in ELs and conventional liposomes to observe the effect of vehicles on in vitro drug-release patterns.…”

“…22,82,83 These drugs are used in the treatment of moderate to severe pain, severe fever, postoperative pain, visceral pain of cancer, edema of traumatic condition, inflammation, and related consequences. However, many side effects have been associated with their use in conventional oral dosage, which limits their clinical efficacy.…”

“…These drugs are associated with gastric disturbances, need frequent administration due to their short biological halflife (4-6 h of ketorolac) leading to several side effects, and there is significant patient noncompliance. 22,83 A report has been published on the delivery of dexamethasone loaded in an EL carrier transdermally, followed by an in vivo study performed in a carrageenan-induced paw edema rat model to show antiedema activity that was better than in conventional liposomes and ointments. Moreover, the study further corroborated the permeation flux and penetration into the rat skin using fluorescence probes (rhodamine 123 and 6-carboxy fluorescein dye).…”