Olive oil and castor oil-based self-nanoemulsifying drug delivery system of flurbiprofen can relieve peripheral pain and inflammation through reduction of oxidative stress and inflammatory biomarkers: a comprehensive formulation and pharmacological insights

Flurbiprofen (FBP) is poorly water-soluble BCS class II drug with anti-inflammatory and analgesic effects, used to treat arthritis and degenerative joint diseases. This study was aimed to develop SNEDDS loaded with FBP. Six SNEDDS using two oils olive oil (F_1OLV, F_2OLV, F_3OLV) and castor oil (F_4CAS, F_5CAS, F_6CAS) with three different Smix ratios consisting of Tween 20 and PEG 400 (1:1, 1:2, 2:1) were prepared and characterized. Compatibility between FBP and polymers was investigated using FTIR. SNEDDS were characterized for physicochemical attributes. Two optimized formulations were investigated at 10 mg/kg dose given orally in Wistar rats for analgesic activity by hot plate and tail flick methods, and anti-inflammatory activity by carrageenan induced paw edema method. Anti-inflammatory activity was further explored by motor coordination and motility by Rota rod and cage activity tests. Following anesthesia blood samples were collected before dissection to measure inflammatory mediators and oxidative stress markers. Sciatica nerves and hind paws of rats were also removed for histopathological evaluation. FTIR studies revealed compatibility of FBP with other components. Droplet size of F_1OLV, F_2OLV, F_3OLV was 128.5 ± 0.7 nm, 202.5 ± 1.3 nm, and 541.5 ± 1.7 nm, whereas it was 142.5 ± 1.1 nm, 215.4 ± 1.2 nm and 349.9 ± 1.8 nm for F_4CAS, F_5CAS, F_6CAS. %EE of F_1OLV, F_2OLV, F_3OLV was found 85 ± 4.89%-91 ± 4.67%, whereas the %EE F_4CAS, F_5CAS, F_6CAS was 84 ± 4.15%-90 ± 4.21%. DSC curves of F_1OLV and F_4CAS revealed amorphous nature of the FBP. SEM showed spherical shape of globules. % of drug released in the pH medium 1.2 for plain FBP, F_1OLV and F_4CAS was 25%, 59% and 57%. % drug released in the pH 6.8 for plain FBP, F_1OLV and F_4CAS was 59%, 85% and 83%. Oral administration of FBP-loaded SNEDDS (F_1OLV and F_4CAS) significantly decreased paw diameter and enhanced motor coordination in rats when compared to the disease control group. This was linked to the ability of FBP to reduce inflammation and oxidative stress, with histological studies indicating decreased tissue damage in SNEDDS treated groups, implying the possibility of tissue recovery. Administration of both formulations started to demonstrate analgesic and anti-inflammatory effects after one hour of administration. In addition to anti-inflammatory effect, both formulations improved motor coordination, motility, and reduced infiltration of inflammatory cells in the inflamed paws. The anti-inflammatory and analgesic activities were attributed to decreased serum levels of IL-6 and TNF-α, increased activity of SOD and reduced nitrite content in sciatic nerves. Histopathological evaluation revealed reduced vascularity, inflammation and synovial hyperplasia. The overall findings suggest that the FBP loaded SNEDDS can be used as carriers for improved delivery of FBP which can effectively be used to cure pain and inflammation.