title: Advantageous Solubility-Permeability Interplay When Using Amorphous Solid Dispersion (ASD) Formulation for the BCS Class IV P-gp Substrate Rifaximin: Simultaneous Increase of Both the Solubility and the Permeability.
abstract: Rifaximin is a BCS class IV (low-solubility, low-permeability) drug and also a P-gp substrate. The aims of this work were to assess the efficiency of different rifaximin amorphous solid dispersion (ASDs) formulations in achieving and maintaining supersaturation and to investigate the consequent solubility-permeability interplay. Spray-dried rifaximin ASDs were prepared with different hydrophilic polymers and their ability to achieve and maintain supersaturation was assessed. Then, rifaximin's apparent intestinal permeability was investigated as a function of increasing supersaturation both in vitro using the parallel artificial membrane permeability assay (PAMPA) and in vivo using the single-pass rat intestinal perfusion (SPIP) model. The efficiency of the different ASDs to achieve and maintain supersaturation of rifaximin was found to be highly polymer dependent, and the copovidone/HPC-SL formulation was found to be superior to the other two, allowing supersaturation of 200× that of the crystalline solubility for 20 h. In vitro, rifaximin flux was increased and the apparent permeability was constant as a function of increasing supersaturation level. In vivo, on the other hand, absorption rate coefficient (ka) was first constant as a function of increasing supersaturation, but at 250×, the crystalline solubility kawas doubled, similar to the kain the presence of the strong P-gp inhibitor GF120918. In conclusion, a new and favorable nature of solubility-permeability interplay was revealed in this work: delivering high supersaturation level of the BCS class IV drug rifaximin via ASD, thereby saturating the drugs' P-gp-mediated efflux transport, led to the favorable unique win-win situation, where both the solubility and the permeability increased simultaneously.
authors.affiliation: Department of Clinical Pharmacology, School of Pharmacy, Faculty of Health Sciences, Ben-Gurion University of the Negev, P.O.Box 653, 84105, Beer-Sheva, Israel.
authors.forename: Avital
authors.initials: A
authors.lastname: Beig
authors.affiliation: Department of Clinical Pharmacology, School of Pharmacy, Faculty of Health Sciences, Ben-Gurion University of the Negev, P.O.Box 653, 84105, Beer-Sheva, Israel.
authors.forename: Noa
authors.initials: N
authors.lastname: Fine-Shamir
authors.affiliation: AbbVie Inc., North Chicago, Illinois, 60064, USA.
authors.forename: David
authors.initials: D
authors.lastname: Lindley
authors.affiliation: AbbVie Inc., North Chicago, Illinois, 60064, USA.|Vertex Pharmaceuticals Inc., 50 Northern Ave, Boston, Massachusetts, 02210, USA.
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Miller
authors.affiliation: Department of Clinical Pharmacology, School of Pharmacy, Faculty of Health Sciences, Ben-Gurion University of the Negev, P.O.Box 653, 84105, Beer-Sheva, Israel. arikd@bgu.ac.il.
authors.forename: Arik
authors.initials: A
authors.lastname: Dahan
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors; D000284:Administration, Oral; D000818:Animals; D000890:Anti-Infective Agents / Q000737:chemistry / Q000493:pharmacokinetics*; D016503:Drug Delivery Systems; D008297:Male; D010539:Permeability; D017208:Rats, Wistar; D012294:Rifamycins / Q000737:chemistry / Q000493:pharmacokinetics*; D000078262:Rifaximin; D012995:Solubility
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000890:Anti-Infective Agents; D012294:Rifamycins; D000078262:Rifaximin
keywords: P-gp; drug absorption; intestinal permeability; low solubility; oral drug delivery; supersaturation