Abstract
Objective: Ranolazine (RZ), antianginal drug indicated for the treatment of chronic stable angina pectoris, was formulated into sustained-release matrix tablets and optimized to improve patient compliance and achieve controlled release over a certain period.
 Methods: Different formulations were prepared by wet- and melt-granulation techniques. Excipients at different ratios as Eudragit® L100-55, Methocel™ E5, Avicel® PH-101, and carnauba wax powder were used to develop a ternary polymeric matrix system for the controlled delivery of RZ. The prepared formulations were subjected to granulometric and characteristic studies. Comparative dissolution and release kinetic studies of the selected formulation and the reference product, Ranexa® extended-release film-coated tablets, Gilead Sciences, Inc., USA, were further carried out to ensure product similarity.
 Results: The optimum pH-dependent to pH-independent polymers ratio was 1:1.3 (w/w). Extragranular carnauba wax in a concentration of 32.50 mg/tablet (2.50 gm% w/w) was the key excipient in controlling drug release kinetics by forming waxy matrix granules which prevent rapid dissolution. Modulation of the microenvironmental pH using a potent alkalinizing agent was very effective for controlling drug release patterns in different dissolution media from pH 1.2–6.8.
 Conclusion: The release of RZ from the matrix tablets was controlled for a period of 24 h, and thereby expected to provide patient compliance with minimal side effects.
Highlights
Chronic stable angina pectoris (CSAP) is the most prevalent manifestation of coronary artery disease that impairs quality of life, and reduces life expectancy, among the elderly
Pre-formulation and preliminary studies Flowability and handling characteristics of the prepared matrix granules were evaluated by the fixed funnel and free-standing cone method to determine the angle of repose (θ), which typically showed good flow properties with θ ranged from 33° to 35° for wet-granulation formulations, and 31° to 33° for melt-granulation formulations
Different pharmaceutical technologies and formulation strategies were preliminarily screened for the preparation of RZ sustained-release tablets, such as direct compression using conventional and highfunctionality excipients, dry-granulation, and wet-granulation using pH-independent polymers only, but only wet- and melt-granulation techniques using a blend of multifunctional polymers with controlled microenvironmental pH, showed the best results in terms of in-vitro drug release and comparative dissolution
Summary
Chronic stable angina pectoris (CSAP) is the most prevalent manifestation of coronary artery disease that impairs quality of life, and reduces life expectancy, among the elderly. 20,000–40,000 individuals of every million population are suffering from CSAP [1]. It is characterized by discomfort in the chest or in adjacent areas, such as jaw, shoulder, back or arms, and usually elicited by exertion or emotional stress [2]. The first-line pharmacological treatment of CSAP includes short-acting nitrates for chest pain relief, as well as β-blockers and Ca2+ antagonists for controlling heart rate and symptoms [3]. Despite the effectiveness of the current treatment regimen, episodes of CSAP may persist or even get worse. A combination of antianginal drugs can cause many gastrointestinal and cardiovascular side effects on long-term use [4,5]. The development of a new antianginal drug with favorable antiarrhythmic properties is a promising approach
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