Etodolac transdermal cubosomes for the treatment of rheumatoid arthritis: ex vivo permeation and in vivo pharmacokinetic studies

Abstract

In this study, transdermal etodolac-loaded cubosomes were developed in order to relieve patient pain and joints stiffness by providing stable etodolac concentration at the targeting sites through controlled drug delivery via the noninvasive skin route with more sustaining and less frequent dosing. Different ratios and percentages of poloxamer 407 and monoolein were used to formulate the cubosomes using emulsification and homogenization processes. The etodolac-loaded cubosomes showed particle size values ranging from 135.95 to 288.35 nm and zeta potential values ranging from -18.40 to -36.10 mV. All the cubosomes offered an encapsulation efficiency value of about 100% and showed drug loading capacity ranging from 1.28 to 6.09%. The in vitro drug release studies revealed a controlled drug release profile with a drug release rate up to 15.08%/h. Increasing poloxamer concentration in etodolac-loaded cubosomes resulted in nanoparticles with less particle size and faster drug release. The particles exhibited cubic and hexagonal shapes. The DSC and X-ray analysis demonstrated that the drug was encapsulated in the cubosomes bicontinuous structures in amorphous form. In addition, investigated cubosomes exhibited fast drug penetration through excited mice skin followed by slower drug penetration for up to 24 h. The pharmacokinetic study in human volunteers showed that the selected etodolac-loaded cubosomes enhanced the bioavailability of etodolac as compared to the oral capsules (266.11%) with evidence of longer half-life and higher MRT that reached 18.86 and 29.55 h, respectively. The etodolac-loaded cubosomes propose a promising system for treatment of arthritis simply through skin application.

Formulation and Evaluation of Cubosomes as Skin Retentive System for Topical Delivery of Clotrimazole

“…The DSC thermogram of clotrimazole exhibited a single sharp characteristic, endothermic peak at about 145 o C, corresponding to its melting point which was in agreement with that reported previously 44 .Such sharp peak indicates the crystalline state of the drug. However, the thermogram of clotrimazole loaded cubic gel revealed the disappearance of the drug melting peak and the appearance of endothermic peak at 71 o C. The disappearance of the drug melting peak indicating that the drug was molecularly encapsulated in the bicontinuous structures in non-crystalline form which was in agreement with that reported previously [45][46] .The appearance of endothermic peak at 71 o C in the thermograms of drug loaded cubic gel as well as blank cubic gel might be due to the phase transition from cubic to reversed hexagonal phase; such transition is known to occur at 71°C [47][48][49] . This finding can be also considered as further confirmation of formation of cubic phase in addition to polarized microscopy and TEM.…”

“…All the investigated formulae(F3-F6)exhibited Newtonian flow behavior with viscosity values ranged from 2.36 ± 0.22 cp to 9.5 ± 0.15 cp as shown in Table 2. Such low viscosity values can increase drug penetration into skin 46 . Also, it can be noticed from comparing the viscosity values of formulae (F4, F5 & F6) that increasing the content of poloxamer 407in the dispersion led to increasing viscosity.…”

“…Also, it can be noticed from comparing the viscosity values of formulae (F4, F5 & F6) that increasing the content of poloxamer 407in the dispersion led to increasing viscosity. This might be due to formation of more solid-like liquid crystal materials 46 . In addition, it was observed that the presence of PVA had a potential effect on increasing the viscosity of the dispersions (F4-F6)in comparison with (F3) that not contain PVA.…”

Cubosomes: The Next Generation of Smart Lipid Nanoparticles?

“…It was found that topical delivery of Etodolac via cubosomes provided controlled delivery at lower dosages but over a prolonged time period in comparison to orally administered Etodolac, and therefore could be a novel method for treating arthritis. [138] Capsaicin is a natural alkaloid used to treat psoriasis and contact allergies and as a formulation to relieve post-operative pain. Cubosomes formed from monoolein or phytantriol, stabilized with F127 and loaded with Capsaicin were used to test percutaneous skin permeation and Capsaicin retention in vitro on the abdominal skin of excised Sprague Dawley rats.…”

Optimization and in Vitro Evaluation of the Release of Class Ii Drug From Its Nanocubosomal Dispersion

“…If the emulsion is o/w type then the addition of more continuous phase (water) will not cause cracking or separation of that emulsion. The results showed that the addition of water to all nanocubosomal dispersion formulas (F1-F10) showed clear nanocubosomal dispersion in less than 1 minute with no cracking or separation adding a further indication that they are all o/w type [27].…”