title: Lipid-based oral delivery systems for skin deposition of a potential chemopreventive DIM derivative: characterization and evaluation.
abstract: The objective of this study was to explore the oral route as a viable potential for the skin deposition of a novel diindolylmethane derivative (DIM-D) for chemoprevention activity. Various lipid-based oral delivery systems were optimized and compared for enhancing DIM-D's oral bioavailability and skin deposition. Preformulation studies were performed to evaluate the log P and solubility of DIM-D. Microsomal metabolism, P-glycoprotein efflux, and caco-2 monolayer permeability of DIM-D were determined. Comparative evaluation of the oral absorption and skin deposition of DIM-D-loaded various lipid-based formulations was performed in rats. DIM-D showed pH-dependent solubility and a high log P value. It was not a strong substrate of microsomal degradation and P-glycoprotein. SMEDDs comprised of medium chain triglycerides, monoglycerides, and kolliphor-HS15 (36.70 ± 0.42 nm). SNEDDs comprised of long chain triglycerides, cremophor RH40, labrasol, and TPGS (84.00 ± 14.14 nm). Nanostructured lipid carriers (NLC) consisted of compritol, miglyol, and surfactants (116.50 ± 2.12 nm). The blank formulations all showed >70 % cell viability in caco-2 cells. Differential Scanning Calorimetry confirmed the amorphization of DIM-D within the lipid matrices while Atomic Force Microscopy showed particle size distribution similar to the dynamic light scattering data. DIM-D also showed reduced permeation across caco-2 monolayer that was enhanced (p < 0.05) by SNEDDs in comparison to SMEDDs and NLC. Fabsolute for DIM-D SNEDDs, SMEDDs, and NLC was 0.14, 0.04, and 0.007, respectively. SNEDDs caused 53.90, 11.32, and 15.08-fold more skin deposition of DIM-D than the free drug, SMEDDs, and NLC, respectively, at 2 h following oral administration and shows a viable potential for use in skin cancer chemoprevention. Graphical Abstract ᅟ.
authors.affiliation: College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, 1520 S Martin Luther King Jr. Blvd, Tallahassee, FL, 32307, USA.
authors.forename: Cedar H A
authors.initials: CH
authors.lastname: Boakye
authors.affiliation: College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, 1520 S Martin Luther King Jr. Blvd, Tallahassee, FL, 32307, USA.
authors.forename: Ketan
authors.initials: K
authors.lastname: Patel
authors.affiliation: College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, 1520 S Martin Luther King Jr. Blvd, Tallahassee, FL, 32307, USA.
authors.forename: Apurva R
authors.initials: AR
authors.lastname: Patel
authors.affiliation: Nanomedicine and Nanotoxicology Group, Physics Institute of São Carlos, USP, São Carlos, SP, 13566-590, Brazil.
authors.forename: Henrique A M
authors.initials: HA
authors.lastname: Faria
authors.affiliation: Nanomedicine and Nanotoxicology Group, Physics Institute of São Carlos, USP, São Carlos, SP, 13566-590, Brazil.
authors.forename: Valtencir
authors.initials: V
authors.lastname: Zucolotto
authors.affiliation: Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, TX, USA.
authors.forename: Stephen
authors.initials: S
authors.lastname: Safe
authors.affiliation: College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, 1520 S Martin Luther King Jr. Blvd, Tallahassee, FL, 32307, USA. mandip.sachdeva@gmail.com.
authors.forename: Mandip
authors.initials: M
authors.lastname: Singh
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D018938:Caco-2 Cells; D002470:Cell Survival / Q000187:drug effects; D002626:Chemistry, Pharmaceutical; D016503:Drug Delivery Systems / Q000379:methods*; D004355:Drug Stability; D004655:Emulsions / Q000008:administration & dosage / Q000737:chemistry; D006801:Humans; D007211:Indoles / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics*; D008055:Lipids; D008297:Male; D008861:Microsomes / Q000378:metabolism; D010316:Particle Size; D051381:Rats; D012867:Skin / Q000378:metabolism; D012995:Solubility
chemical_list: C534880:1,1-bis(3'-indolyl)-1-(4-chlorophenyl)methane; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D004655:Emulsions; D007211:Indoles; D008055:Lipids
keywords: Diindolylmethane (DIM); First pass metabolism; Lipid-based drug delivery systems; Oral delivery; P-glycoprotein efflux pump; Skin delivery