title: Formulation and development of bicontinuous nanostructured liquid crystalline particles of efavirenz.
abstract: Efavirenz is a lipophilic non-nucleoside reverse transcriptase inhibitor used in the first-line pediatric therapeutic cocktail. Due to its high lipophilicity (logP = 5.4) and poor aqueous solubility (intrinsic water solubility = 8.3 μg/mL) efavirenz has low bioavailability. A 30 mg/mL solution in a medium-chain triglyceride vehicle is the only pediatric formulation available with an oral bioavailability 20% lower than the solid form. The current work was aimed at formulating and characterizing liquid crystal nanoparticles for oral delivery of efavirenz to improve oral bioavailability, provide sustained release, minimize side effects and drug resistance. Formulation of cubosomes was done by two methods; sonication and spray drying. Sonication gave highest entrapment efficiency and least particle size. Further, monoolein was substituted with phytantriol as monoolein gets degraded in the presence of lipase when administered orally with consequent loss of liquid crystalline structure. It was confirmed that there was no difference in particle size, entrapment efficiency and nature of product formed by using monoolein or phytantriol. The best formulation was found to be F9, having particle size 104.19 ± 0.21 nm and entrapment efficiency 91.40 ± 0.10%. In vitro release at the end of 12h was found to be 56.45% and zeta potential to be -23.14 mV which stabilized the cubic phase dispersions. It was further characterized for TEM, small angle X-ray scattering (SAXS), DSC and stability studies. SAXS revealed Pn3m space group, indicating a diamond cubic phase which was further confirmed by TEM. Pharmacokinetics of EFV was studied in male Wistar rats. EFV-loaded cubosome dispersions exhibited 1.93 and 1.62-fold increase in peak plasma concentration (Cmax) and 1.48 and 1.42-fold increase in AUC in comparison to that of a suspension prepared with the contents of EFV capsules suspended in 1.5% carboxymethylcellulose PBS solution (pH 5.0), and an EFV solution in medium-chain triglyceride respectively. Thus, stable cubosomes of efavirenz with increased bioavailability providing sustained release effect could be prepared successfully using phytantriol and poloxamer 407.
authors.affiliation: Department of Pharmaceutics, Sinhgad College of Pharmacy, Vadgaon (Bk), Pune, India. Electronic address: prof_avachat@yahoo.com.
authors.forename: Amelia M
authors.initials: AM
authors.lastname: Avachat
authors.affiliation: Department of Pharmaceutics, Sinhgad College of Pharmacy, Vadgaon (Bk), Pune, India. Electronic address: shreeparpani@gmail.com.
authors.forename: Shreekrishna S
authors.initials: SS
authors.lastname: Parpani
mesh_terms: D000480:Alkynes; D000818:Animals; D048588:Benzoxazines / Q000097:blood / Q000737:chemistry* / Q000493:pharmacokinetics; D003521:Cyclopropanes; D050866:Liquid Crystals / Q000737:chemistry*; D008297:Male; D049329:Nanostructures / Q000737:chemistry*; D010316:Particle Size; D004364:Pharmaceutical Preparations / Q000097:blood / Q000737:chemistry*; D051381:Rats; D017208:Rats, Wistar; D012995:Solubility; D013499:Surface Properties
chemical_list: D000480:Alkynes; D048588:Benzoxazines; D003521:Cyclopropanes; D004364:Pharmaceutical Preparations; C098320:efavirenz
keywords: Cubic phase; Cubosomes; Efavirenz; Liquid crystal; Monoolein; Sustained release