Design of fixed dose combination and physicochemical characterization of enteric-coated bilayer tablet with circadian rhythmic variations containing telmisartan and pravastatin sodium.
The aim of this study was to investigate a fixed dose combination (FDC) of telmisartan (TEL) and pravastatin sodium (PRA) in enteric-coated bilayer tablets, which was designed for once-daily bedtime dose in order to match circadian rhythmic variations of hypertension and cholesterol synthesis and optimize the patient friendly dosing treatment. Due to the poor aqueous solubility of TEL, ternary solid dispersions (SD) consisting of TEL, polyethylene glycol 6000 (PEG 6000) and magnesium oxide (MgO) were designed to enhance its dissolution rate in intestinal fluid. MgO was added as an effective alkalizer to maintain the high microenvironmental pH of the saturated solution in the immediate vicinity of TEL particles because TEL is known to be ionizable but poorly soluble in intestinal fluid. In contrast, PRA is known to be very unstable in low pH conditions. In the SD system, TEL was present in an amorphous structure and formed an intermolecular hydrogen bonding with MgO, giving complete drug release without precipitation in intestinal fluid. In addition, the amount of hydrophilic carrier (PEG 6000) was also a factor. In the design of tablet formulation, the diluents and superdisintegrants could play a key role in release profiles. Then, to fulfill the unmet needs of the two model drugs and match circadian rhythmic variations of hypertension and cholesterol synthesis, enteric-coated bilayer tablet consisting of TEL SD and PRA was finally prepared using Acryl-EZE®as an enteric coating material. Prior to enteric coating, a seal coating layer (Opadry®, 2% weight gains) was firstly introduced to separate the core bilayer tablet from the acidic enteric coating polymers to avoid premature degradation. Dissolution profiles of finished tablets revealed that enteric-coated bilayer tablets with 6% weight gains remained intact in acidic media (pH 1.0) for 2h and then released drugs completely within 45min after switching to the intestinal media (pH 6.8). It was observed that enteric-coated bilayer tablets were stable during 3 month under the accelerated condition of 40°C/75% RH. The delayed drug release and bedtime dosage regimen using enteric-coated bilayer tablet containing TEL and PRA, matching the circadian rhythms of hypertension and hyperlipidemia can provide therapeutic benefits for elderly patients in terms of maximizing the therapeutic effects.
College of Pharmacy, Ajou University, Suwon, 16499, Republic of Korea.
Daoqi
D
Luo
College of Pharmacy, Ajou University, Suwon, 16499, Republic of Korea.
Joo Hee
JH
Kim
College of Pharmacy, Ajou University, Suwon, 16499, Republic of Korea.
Chulhun
C
Park
College of Pharmacy, The Catholic University, Bucheon, 420-743, Republic of Korea.
Euichaul
E
Oh
College of Pharmacy, Sahmyook University, Seoul, 01795, Republic of Korea.
Jun-Bom
JB
Park
College of Pharmaceutical Science, Soochow University, Suzhou, 215123, China.
Jing-Hao
JH
Cui
College of Pharmaceutical Science, Soochow University, Suzhou, 215123, China.
Qing-Ri
QR
Cao
College of Pharmacy, Ajou University, Suwon, 16499, Republic of Korea; Institute of Pharmaceutical Science and Technology, Ajou University, Suwon, 16499, Republic of Korea. Electronic address: bjl@ajou.ac.kr.
Beom-Jin
BJ
Lee
D000924:Anticholesteremic Agents / Q000008:administration & dosage / Q000737:chemistry*; D000959:Antihypertensive Agents / Q000008:administration & dosage / Q000737:chemistry*; D001562:Benzimidazoles / Q000008:administration & dosage / Q000737:chemistry*; D001565:Benzoates / Q000008:administration & dosage / Q000737:chemistry*; D055870:Drug Chronotherapy; D004338:Drug Combinations; D065546:Drug Liberation; D004355:Drug Stability; D033362:Powder Diffraction; D017035:Pravastatin / Q000008:administration & dosage / Q000737:chemistry*; D013608:Tablets, Enteric-Coated; D000077333:Telmisartan; D014961:X-Ray Diffraction
D000924:Anticholesteremic Agents; D000959:Antihypertensive Agents; D001562:Benzimidazoles; D001565:Benzoates; D004338:Drug Combinations; D013608:Tablets, Enteric-Coated; D017035:Pravastatin; D000077333:Telmisartan
Circadian rhythmic variations; Delayed release; Enteric-coated bilayer tablet; Fixed dose combination enhanced telmisartan dissolution; Patient friendly therapeutic benefits; Pravastatin sodium