Lipitor

Mindray Resona 7S color Doppler ultrasound diagnostic instrument (L14-5WU probe; Mindray Bio-Medical Electronics Co., Ltd., Shenzhen, China); TomTec 2D-STI analysis software (TomTec Imaging Systems GmbH, Unterschleissheim, Germany), small animal ventilator (RWD Life Technology Co., Ltd., Shenzhen, China); electrocardiogram (ECG) machine with BL-420 bio-signal collection system (Chengdu Techman Technology Co., Ltd., Chengdu, China); 10% chloral hydrate (prepared by Xiangyang No. 1 People's Hospital, Hubei University of Medicine); H&E dye liquor (Nanjing Jiancheng Biological Engineering Institute); Ator calcium tablets (trade name: Lipitor, Pfizer Pharmaceutical Co., Ltd.).

This was a randomized, open-label, multiple-dose, three-treatment, three-period, Williams design crossover study (Fig. 1). The IPs were atorvastatin calcium (40 mg, Lipitor®, Pfizer Korea Ltd.) and ezetimibe (10 mg, Ezetrol®, MSD Korea Ltd.). All subjects were randomly assigned to one of the following six treatment sequences: ABC, ACB, BCA, BAC, CAB, or CBA with an 11-day washout period between treatments A, B, and C. The treatment regimens were once daily administrations of atorvastatin 40 mg (treatment A), ezetimibe 10 mg (treatment B), or co-administration of atorvastatin 40 mg and ezetimibe 10 mg (treatment C) for seven days. The subjects visited the outpatient clinic at 8 am each morning, and were orally administered the assigned IP with 240 mL water at the fasted state for the first six days of each period (D1~D6, D18~D23, and D35~D40). They were hospitalized in the afternoon on the 6^th day of each period for intensive PK sampling and safety assessment. After overnight fasting, the 7^th dose of the IP was orally administered with 240 mL water; all subjects were prohibited from drinking water for 1 h before and after IP administration. After fasting for 4 h post-dose, a standard meal (700–800 kcal and 5–25% fat) was served to all subjects at 4 and 10 h after dosing.

Atorvastatin (ATR) was a gift sample from Jamjoom Pharma, Saudi Arabia. Chitosan of different molecular weights (CS_L-40, CS_M-480, CS_H-850 kDa); viscosities (20, 200, and 800 cps); degree of deacetylation (92, 82, and 77) and poloxamer 407 were purchased from Sigma-Aldrich Co., St Louis, MO, USA. Labrasol^® was received as gift from Gattefosse Co. (Saint Priest Cedex, France). Lipitor^® (Pfizer. Inc., New York, NY, USA) 80 mg strip was a gift sample from King Abdulaziz Hospital, Saudi Arabia. Biochemical analysis kits to estimate total cholesterol, triglycerides, high density lipoprotein (HDL) and low density lipoprotein (LDL) levels were purchased from United Diagnostics Industry, Saudi Arabia. Organic solvents like acetonitrile, acetic acid, and methanol used were of analytical grade, purchased from Sigma-Aldrich Co. All other chemicals and solvents were of analytical grade. Deionized and distilled water was used throughout the study.