title: Formulation and process optimization of multiparticulate pulsatile system delivered by osmotic pressure-activated rupturable membrane.
abstract: In this study, a multiparticulate pulsatile drug delivery system activated by a rupturable controlled-release membrane (Eudragit(®) RS) via osmotic pressure (with NaCl as the osmogent) was developed and characterized for omeprazole, omeprazole sodium, and propranolol HCl which have different water solubilities. Multiparticulates in pellet form for incorporation with or without the osmogent were manufactured by three methods and then used to coat a polymeric membrane. Results demonstrated that drug/osmogent-containing pellets manufactured by the extrusion/spheronization method with incorporation of the osmogent were optimal. The lag time (tL) to initiate pulsatile release is regulated by tL=l(2)/(6×D), which is dependent on the coating levels (l(2)) and plasticizer content (D). The pulsatile release pattern was found to be dependent on the osmotic pressure (osmogent), drug solubility, and mechanical properties of the polymeric membrane (elasticity and toughness). Omeprazole with lower water solubility could not generate sufficient osmotic pressure to create a crack in the membrane to activate pulsatile release, whereas the two other model drugs with higher solubilities could. But adsorption of omeprazole sodium on Eudragit(®) RS via charge-charge interactions led the its incomplete release. Finally, with 4% osmogent of NaCl added, a lag time in a range from 0 to 12h proportionally regulated by varying both the membrane thickness and plasticizer level initiated the complete pulsatile release of propranolol HCl. In conclusion, a multiparticulate pulsatile drug delivery system activated by a rupturable controlled-release membrane via osmotic pressure was successfully developed, and clinical applications of chronotherapy with drugs like propranolol HCl are expected.
authors.affiliation: School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei, Taiwan.
authors.forename: Sheng-Feng
authors.initials: SF
authors.lastname: Hung
authors.affiliation: Department of Cosmetic Science, Providence University, Taichung City, Taiwan.
authors.forename: Chien-Ming
authors.initials: CM
authors.lastname: Hsieh
authors.affiliation: School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei, Taiwan.
authors.forename: Ying-Chen
authors.initials: YC
authors.lastname: Chen
authors.affiliation: School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei, Taiwan.
authors.forename: Cheng-Mao
authors.initials: CM
authors.lastname: Lin
authors.affiliation: School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei, Taiwan. Electronic address: hsiuoho@tmu.edu.tw.
authors.forename: Hsiu-O
authors.initials: HO
authors.lastname: Ho
authors.affiliation: School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei, Taiwan; Clinical Research Center and Traditional Herbal Medicine Research Center, Taipei Medical University Hospital, Taipei, Taiwan. Electronic address: mingsheu@tmu.edu.tw.
authors.forename: Ming-Thau
authors.initials: MT
authors.lastname: Sheu
mesh_terms: D000180:Acrylic Resins / Q000737:chemistry; D002626:Chemistry, Pharmaceutical / Q000379:methods; D003692:Delayed-Action Preparations; D004339:Drug Compounding / Q000379:methods; D016503:Drug Delivery Systems; D065546:Drug Liberation; D005079:Excipients / Q000737:chemistry; D009853:Omeprazole / Q000008:administration & dosage* / Q000737:chemistry; D009997:Osmotic Pressure; D011108:Polymers / Q000737:chemistry; D011433:Propranolol / Q000008:administration & dosage* / Q000737:chemistry; D012995:Solubility; D013997:Time Factors
chemical_list: D000180:Acrylic Resins; D003692:Delayed-Action Preparations; D005079:Excipients; D011108:Polymers; C050528:Eudragit RS; D011433:Propranolol; D009853:Omeprazole
keywords: Eudragit(®) RS; Lag time; Multiparticulate; Osmotic pressure; Pulsatile release