title: PD-PK evaluation of freeze-dried atorvastatin calcium-loaded poly-ε-caprolactone nanoparticles.
abstract: In this work lyophilized poly-ε-caprolactone nanoparticles (NPs) loaded with atorvastatin calcium (AC) were developed in an attempt to improve the in-vivo performance of AC following oral administration. The individual and combined effects of several formulation variables were previously investigated using step-wise full factorial designs in order to produce optimized AC-NPs with predetermined characteristics including particle size, drug loading capacity, drug release profile and physical stability. Four optimized formulations were further subjected in this work to lyophilization to promote their long-term physical stability and were fully characterized. The pharmacodynamics (PD)/pharmacokinetics (PK) properties of two optimized freeze-dried AC-NPs formulations showing acceptable long-term stability were determined and compared to a marketed AC immediate release tablet (Lipitor(®)) in albino rats. PD results revealed that the two tested formulations were equally effective in reducing low density lipoproteins (LDL) and triglycerides (TG) levels when given in reduced doses compared to Lipitor(®) and showed no adverse effects. PK results, on the other hand, revealed that the two freeze-dried AC-NPs formulations were of significantly lower bioavailability compared to Lipitor(®). Taken together the PD and PK results demonstrate that the improved efficacy obtained at reduced doses from the freeze-dried AC-NPs could be due to increased concentration of AC in the liver rather than in the plasma.
authors.affiliation: Department of Pharmaceutics & Pharmaceutical Technology, College of Pharmacy, University of Sharjah, Sharjah 27272, United Arab Emirates; Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Cairo University, Cairo 11562, Egypt. Electronic address: iahmed@sharjah.ac.ae.
authors.forename: Iman S
authors.initials: IS
authors.lastname: Ahmed
authors.affiliation: National Organization for Drug Control and Research, Cairo, Egypt.
authors.forename: Rania
authors.initials: R
authors.lastname: El-Hosary
authors.affiliation: National Organization for Drug Control and Research, Cairo, Egypt.
authors.forename: Samia
authors.initials: S
authors.lastname: Shalaby
authors.affiliation: National Organization for Drug Control and Research, Cairo, Egypt.
authors.forename: Marwa M
authors.initials: MM
authors.lastname: Abd-Rabo
authors.affiliation: National Organization for Drug Control and Research, Cairo, Egypt.
authors.forename: Dalia G
authors.initials: DG
authors.lastname: Elkhateeb
authors.affiliation: Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Cairo University, Cairo 11562, Egypt.
authors.forename: Samia
authors.initials: S
authors.lastname: Nour
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000924:Anticholesteremic Agents / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D000069059:Atorvastatin / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D002784:Cholesterol / Q000097:blood; D003692:Delayed-Action Preparations / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D065546:Drug Liberation; D005612:Freeze Drying; D008297:Male; D053758:Nanoparticles / Q000008:administration & dosage* / Q000737:chemistry; D010316:Particle Size; D011091:Polyesters / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D014280:Triglycerides / Q000097:blood
chemical_list: D000924:Anticholesteremic Agents; D003692:Delayed-Action Preparations; D011091:Polyesters; D014280:Triglycerides; C016240:polycaprolactone; D002784:Cholesterol; D000069059:Atorvastatin
keywords: Atorvastatin calcium; Freeze-drying; Nanoparticles; Pharmacodynamics/pharmacokinetic studies