title: Systematic development of solid self-nanoemulsifying oily formulations (S-SNEOFs) for enhancing the oral bioavailability and intestinal lymphatic uptake of lopinavir.
abstract: The present studies entail the development of the systematically optimized solid self-nanoemulsifying oily formulations (S-SNEOFs) for enhancing the systemic bioavailability of lopinavir and targeting the same to the sanctuary site, i.e., lymphatic system for complete HIV inhibition. The patient-centric quality target product profile (QTPP) was defined and critical quality attributes (CQAs) earmarked. Risk assessment studies, carried out through failure mode and effect critically analysis (FMECA), helped in identifying the plausible risks or failure modes affecting the quality attributes of the drug product. As per the preliminary studies, viz solubility and phase titration studies, and factor screening studies, Maisine (i.e., lipid), Tween 80 (emulgent), Transcutol HP (i.e., cosolvent) were selected as the critical material attributes (CMAs) of the liquid SNEOFs (L-SNEOFs). D-optimal mixture design was employed for the optimization of aforesaid CMAs and evaluated for in vitro dissolution, globule size, ex vivo permeation studies as the critical quality attributes (CQAs). Optimal composition of CMAs, was embarked through numerical optimization and desirability function, exhibited excellent permeation and drug release characteristics besides possessing globule size in nano range, i.e., 53.16 nm. Further to increase the stability and drug loading, the OPT-L-SNEOFs were then adsorbed onto the porous carrier, i.e., Aeroperl, to prepare the OPT-SNEOF tablets which were finally compressed into the tablet employing MCC as the filler. The performance evaluation through in situ SPIP studies ascribed the significant enhancement in absorptivity parameters of both the SNEOFs vis-à-vis the pure drug. Also, chylomicron flow block SPIP studies revealed lymphatic uptake of lopinavir from the SNEOFs. Overall, in vivo pharmacokinetic studies in rats revealed significant improvement in the rate and extent of oral bioavailability of the SNEOFs compared to the pure drug. These studies further substantiate the intestinal lymphatic transport of lopinavir for the management of the sanctuary site HIV. In a nutshell, the SNEOFs offer a complete and holistic solution for the management of the viral loads in the lymph and blood.
authors.affiliation: University Institute of Pharmaceutical Sciences, UGC Centre of Advanced Studies, Panjab University, Chandigarh 160 014, India.
authors.forename: Babita
authors.initials: B
authors.lastname: Garg
authors.affiliation: University Institute of Pharmaceutical Sciences, UGC Centre of Advanced Studies, Panjab University, Chandigarh 160 014, India.
authors.forename: O P
authors.initials: OP
authors.lastname: Katare
authors.affiliation: University Institute of Pharmaceutical Sciences, UGC Centre of Advanced Studies, Panjab University, Chandigarh 160 014, India.
authors.forename: Sarwar
authors.initials: S
authors.lastname: Beg
authors.affiliation: UGC-Centre of Excellence in Applications of Nanomaterials, Nanoparticles & Nanocomposites Biomedical Sciences, Panjab University, Chandigarh 160 014, India.
authors.forename: Shikha
authors.initials: S
authors.lastname: Lohan
authors.affiliation: University Institute of Pharmaceutical Sciences, UGC Centre of Advanced Studies, Panjab University, Chandigarh 160 014, India; UGC-Centre of Excellence in Applications of Nanomaterials, Nanoparticles & Nanocomposites Biomedical Sciences, Panjab University, Chandigarh 160 014, India. Electronic address: bsbhoop@yahoo.com.
authors.forename: Bhupinder
authors.initials: B
authors.lastname: Singh
mesh_terms: D000284:Administration, Oral; D000818:Animals; D019540:Area Under Curve; D001682:Biological Availability; D065546:Drug Liberation; D045703:Emulsifying Agents / Q000737:chemistry; D004655:Emulsions / Q000737:chemistry*; D017320:HIV Protease Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D007413:Intestinal Mucosa / Q000378:metabolism*; D061466:Lopinavir / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D008208:Lymphatic System / Q000378:metabolism*; D008297:Male; D008657:Metabolic Clearance Rate; D046529:Microscopy, Electron, Transmission; D053758:Nanoparticles / Q000737:chemistry* / Q000648:ultrastructure; D009824:Ointments / Q000737:chemistry; D017208:Rats, Wistar
chemical_list: D045703:Emulsifying Agents; D004655:Emulsions; D017320:HIV Protease Inhibitors; D009824:Ointments; D061466:Lopinavir
keywords: Bioavailability; Biodistribution; Chylomicron flow block model; In situ single pass intestinal perfusion; Quality by design (QbD); SNEDDS