Drug Design, Development and Therapy (May 2021)

Fixed Dose Single Tablet Formulation with Differential Release of Amlodipine Besylate and Simvastatin and Its Pharmacokinetic Profile: QbD and Risk Assessment Approach

  • Kanwal U,
  • Mukhtar S,
  • Waheed M,
  • Mehreen A,
  • Abbas N,
  • Shamim R,
  • Hussain K,
  • Rasool F,
  • Hussain A,
  • Bukhari NI

Journal volume & issue
Vol. Volume 15
pp. 2193 – 2210

Abstract

Read online

Ummarah Kanwal,1 Shahid Mukhtar,1 Muzzamil Waheed,2 Arifa Mehreen,3 Nasir Abbas,1 Rahat Shamim,1 Khalid Hussain,1 Fatima Rasool,1 Amjad Hussain,1 Nadeem Irfan Bukhari1 1Punjab University College of Pharmacy, University of the Punjab, Lahore, Pakistan; 2Government College University, Faisalabad, 38850, Pakistan; 3University of Lahore, Lahore, PakistanCorrespondence: Nadeem Irfan BukhariPunjab University College of Pharmacy, University of the Punjab, Allama Iqbal Campus, Lahore, 54000, PakistanTel +923004259738Email [email protected]: A differential release fixed dose matrix tablet of amlodipine besylate (AML-B) and simvastatin (SIM) was formulated to enhance patient compliance.Material and Method: In the first phase, release controlling parameters of AML-B and SIM granules were identified and in the second phase a fixed dose AML-B and SIM tablet formulation was prepared and optimized for a differential release of the drugs using a quality by design (QbD) and risk assessment approach. A validated HPLC method was employed for simultaneous determination of AML-B and SIM for FDC formulation. A pharmacokinetics of the above drugs was studied in healthy dogs in the third phase.Results: In QbD-based optimized formulation, Eudragit® RSPO-dicalcium phosphate (DCP) blend controlled the release of AML-B over 8 h, though this diffusion-controlled release assumed first order kinetics. DCP and Eudragit® RS 100 also retarded release of SIM causing SIM release over 8 h after AML-B release from the optimized FDC tablet formulation. The HPLC retention times of AML-B and SIM were 2.10 and 15.52 min, respectively. Linearity for AML-B was 5.0– 50 ng/mL and 0.01– 2.0 μg/mL for SIM with percent recoveries of 92.85– 101.53% and 94.51– 117.75% for AML-B and SIM. AUC0-∞ of AML-B was increased 3 fold, while AUC0-∞ of SIM was decreased 2 fold. The tmax values for AML-B and SIM were 12 and 6 h, respectively. AML-B was absorbed without any lag time (tlag) while tlag was 6.33 ± 0.81 h for SIM, thus met the study objective.Conclusion: The pharmacokinetic study showed an immediate absorption of AML-B while that of SIM was withheld for 6 h, close to the desired delay time of 8 h.Keywords: differential release, Eudragit S100, Eudragit RSPO, DCP-Eudragit blend, quality by design, polymers, amlodipine besylate, simvastatin

Keywords