title: Oral delivery of paclitaxel nanocrystal (PNC) with a dual Pgp-CYP3A4 inhibitor: preparation, characterization and antitumor activity.
abstract: Several molecular inheritances have severely restrained the peroral delivery of taxanes. The main objective of the present investigation was to develop a paclitaxel (PTX) formulation which can circumvent the hurdles of its extremely poor solubility and permeability, Pgp efflux and high pre-systemic metabolism. Positively charged PTX nanocrystals of 209 nm were prepared by sonoprecipitation with high pressure homogenization technique, wherein an arginine based surfactant was explored as a stabilizer. The BET surface area analysis revealed that the surface area of PNC was 8.53 m(2)/gm, reflecting significant rise in surface area with nanonization of PTX. The DSC and XRD pattern suggested that the PTX is in the form of the most stable dihydrate crystal. The PNC showed very rapid dissolution profile compared to plain PTX in both sinks and non-sink conditions. Clarithromycin (CLM) was evaluated as a better alternative to cyclosporin A in improving PTX permeability. The PNC-CLM showed remarkable enhancement of 453% in relative bioavailability along with maintaining the therapeutic concentration of PTX for 8h. Efficacy data in B16 F10 melanoma tumor bearing mice showed substantial reduction in tumor volume and improvement in percentage survival compared to the control group.
authors: Department of Pharmaceutical Sciences and Technology, Institute of Chemical Technology, University Under Section 3 of UGC Act-1956, Elite Status and Center of Excellence - Government of Maharashtra, TEQIP Phase II Funded, Matunga (E), Mumbai 400019, India.
authors: Ketan
authors: K
authors: Patel
authors: Clinical Pharmacology, Tata Memorial Centre, Advanced Center for Treatment, Research and Education in Cancer (ACTREC), Kharghar, Navi Mumbai 410210, India.
authors: Anand
authors: A
authors: Patil
authors: Clinical Pharmacology, Tata Memorial Centre, Advanced Center for Treatment, Research and Education in Cancer (ACTREC), Kharghar, Navi Mumbai 410210, India.
authors: Miten
authors: M
authors: Mehta
authors: Clinical Pharmacology, Tata Memorial Centre, Advanced Center for Treatment, Research and Education in Cancer (ACTREC), Kharghar, Navi Mumbai 410210, India.
authors: Vikram
authors: V
authors: Gota
authors: Department of Pharmaceutical Sciences and Technology, Institute of Chemical Technology, University Under Section 3 of UGC Act-1956, Elite Status and Center of Excellence - Government of Maharashtra, TEQIP Phase II Funded, Matunga (E), Mumbai 400019, India. Electronic address: pr.vavia@ictmumbai.edu.in.
authors: Pradeep
authors: P
authors: Vavia
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors*; D000284:Administration, Oral; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage* / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics; D001120:Arginine / Q000031:analogs & derivatives / Q000737:chemistry; D002645:Chickens; D017291:Clarithromycin / Q000008:administration & dosage*; D016572:Cyclosporine / Q000008:administration & dosage; D065692:Cytochrome P-450 CYP3A Inhibitors / Q000008:administration & dosage*; D004339:Drug Compounding; D041981:Gastrointestinal Tract / Q000473:pathology; D065347:Hypromellose Derivatives / Q000737:chemistry; D007082:Ileum / Q000378:metabolism; D008546:Melanoma, Experimental / Q000188:drug therapy / Q000473:pathology; D051379:Mice; D053758:Nanoparticles / Q000008:administration & dosage* / Q000737:chemistry; D017239:Paclitaxel / Q000008:administration & dosage* / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics; D010316:Particle Size; D017207:Rats, Sprague-Dawley; D012878:Skin Neoplasms / Q000188:drug therapy / Q000473:pathology; D013499:Surface Properties; D047368:Tumor Burden / Q000187:drug effects
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000972:Antineoplastic Agents, Phytogenic; D065692:Cytochrome P-450 CYP3A Inhibitors; D065347:Hypromellose Derivatives; D016572:Cyclosporine; D001120:Arginine; D017291:Clarithromycin; D017239:Paclitaxel
keywords: Cationic nanoparticles; Nanosuspension; Oral anticancer; Oral delivery; Paclitaxel; Pgp inhibitors