Colon-Targeted Layer-by-Layer Self-assembled Film: Pharmacokinetic Analysis of BCS Class I and Class III Model Drugs.

The aim of the study was to investigate the pharmacokinetic parameters of 5-fluorouracil (5FU) and moxifloxacin HCl (MF) after oral administration using layer-by-layer assembled film in enteric-coated capsule. The layer-by-layer (LbL) film was prepared by sequential layering of chitosan and sodium alginate polyelectrolytes containing either 5FU or MF. The films were in vitro evaluated for physical characteristics, drug loading and release behaviour. In vivo pharmacokinetic evaluation was performed in the rat model for three different drug concentrations after oral administration and compared with intravenous administration. The results showed that the thickness of 10-bilayer film was 147 ± 11.66 µm and 212.3 ± 7.19 µm after 5FU and MF loading, respectively. The LbL film with backing layer provided directional release of 5FU and MF, where 63.81 ± 4.52% and 101.38 ± 5.08%, respectively, was released in 24 h. 5FU showed non-linear pharmacokinetics compared with linear pharmacokinetics shown by MF after oral administration. There is a dose-dependent increase in Cmax after oral administration of 5FU and MF LbL film. The Tmax was found to be 720 min and 840 min for 5FU and MF after oral administration. The mean residence time and AUC0-24 at 45 mg/kg were 871.4 ± 6.45 min and 198.6 ± 5.03 × 103 min per ng/mL and 1267 ± 142.4 min and 1590 ± 55.60 103 min per ng/mL for 5FU and MF, respectively. Taken together, colon-targeted LbL film can be developed for oral administration of drugs for local and systemic applications.

Transfersome Hydrogel Containing 5-Fluorouracil and Etodolac Combination for Synergistic Oral Cancer Treatment.

Oral cancer is one of the most common malignancies with an increased rate of incidence. 5-Fluorouracil (5FU) is an effective chemotherapeutic indicated for oral cancer treatment. Etodolac (Et), a cyclooxygenase-2 inhibitor, can be used as an adjuvant agent to sensitize cancer cells to chemotherapy. The aim of this work was to prepare and characterize 5FU and Et dual drug-loaded transfersomes to treat oral cancer. Transfersomes were prepared by thin-film hydration method and characterized for the average particle size and zeta-potential using dynamic light scattering and scanning electron microscopy techniques. The prepared transfersomes were further characterized for their drug loading, entrapment efficiencies using amicon centrifuge tubes and drug release behavior using cellulose membrane. The synergistic activity of dual drug-loaded transfersomes was studied in FaDu oral cancer cells. Results showed that the average particle size, polydispersity index, and zeta potential were 91±6.4 nm, 0.28±0.03, and (-)46.9±9.5 mV, respectively, for 5FU- and Et (1:1)-loaded transfersomes. The highest encapsulation efficiency achieved was 36.9±3.8% and 79.8±6.4% for 5FU and Et (1:1), respectively. Growth inhibition studies in FaDu cells using different concentrations of 5FU and Et showed a combination index of 0.36, indicating a synergistic effect. The FaDu cell uptake of drug-loaded transfersomes was significantly (p<0.05) greater than that of free drugs. The transfersome hydrogel made of HPMC (2% w/w) showed similar flux, lag time, and permeation coefficient as that of drug-loaded transfersomes across excised porcine buccal tissue. In conclusion, 5FU and Et transfersome hydrogel can be developed for localized delivery to treat oral cancer.

High fructose and streptozotocin induced diabetic impairments are mitigated by Indirubin-3-hydrazone via downregulation of PKR pathway in Wistar rats.

Metabolic disorders are becoming more common in young population due to increased consumption of carbohydrate rich diet, lack of physical activity and stress. Fructose is used as a sweetener in many carbonated beverages and is a known inducer of oxidative stress and hypertension. Up-regulation of the double-stranded RNA-dependent protein kinase (PKR) causes impairment in insulin signaling pathway and metabolic dysfunctions in type 2 diabetes mellitus. In the present study we investigated the role of PKR and associated pathways in high fructose (HF) and streptozotocin (STZ) induced diabetes and whether indirubin-3-hydrazone (IHZ), a novel PKR inhibitor can reverse the HF and STZ induced diabetic impairments in Wistar rats. Diabetes was induced by feeding rats 20% high fructose in drinking water for 6 weeks and by giving a single dose of STZ (35 mg/kg., i.p) at the end of week 5. Glucose and lipid levels were measured by using assay kits. Expression of PKR and its downstream genes were determined by immunohistochemistry, qRT-PCR and western blotting techniques. Histo-pathological studies were performed using H&E staining. Fibrosis was detected in insulin sensitive tissues and organs using Sirius red and Masson's trichrome staining and apoptosis by TUNEL assay. HF and STZ induced hyperglycemia, fibrosis, oxidative stress, and inflammation in liver, pancreas, skeletal muscle and adipose tissue are mediated via PKR pathway and its downstream effectors, and these effects were attenuated by PKR inhibitor IHZ. Thus, inhibition of PKR can protect insulin sensitive organs and tissues from HF induced diabetic impairments via the inhibition of c-Jun N-terminal kinase (JNK) pathway.