Formulation Optimization of Gastro-Retention Tablets of Paeonol and Efficacy in Treatment of Experimental Gastric Ulcer

Abstract

This study aims to develop a gastroretentive sustained-release drug delivery system of paeonol using floating properties and to investigate its therapeutic effects in rat models. The gastric retention tablets of paeonol (GRT-Ps) were prepared by a direct compression method, and the Box-Behnken design was used to optimize its formulation. The optimized formulation containing 15% NaHCO 3 and a 2 : 1 ratio of paeonol and HPMC-K4M floated within 1 min and remained afloat for more than 8 h in the simulated gastric fluid (200 mL, pH 1.2) and simultaneously showed the desired sustained drug release. Moreover, small tablets (3 mm) were prepared according to the same formulation and the process technology of big tablets (8 mm). A similar drug release behavior was observed between two kinds of tablets ( f 2 52), and then the evaluations of efficacy and retention capacity in vivo were conducted with small tablets. In vivo retention studies showed that the T max (2 h) of GRT-P in rat stomachs was significantly extended compared with the T max (0.5 h) of normal reference preparation. Compared with the model group, low and high doses of GRT-P could significantly inhibit the increase of malondialdehyde (MDA) in serum. Studies showed that the higher MDA content in inflammation tissue increases the inflammatory response. The ulcer inhibition rates of GRT-P in the highdose group were 59.0 and 64.1% in the ranitidine group. Results indicated that GRT-Ps had the potential for a sustained drug release and an enhanced gastric residence time with relatively high drug concentrations in the tissue distribution.Key words paeonol; gastric retention tablet; sustained release; gastric ulcer; efficacy Paeonol, also called peony phenol, is the active component of a traditional Chinese medicine, namely, moutan cortex (Paeonia suffruticosa ANDREWS, Ranunculaceae).1) Paeonol has been extensively studied for its anti-inflammatory, antioxidant, anti-atherosclerosis, anti-diabetic, and anti-mutagenic effects.2,3) However, paeonol has significant growth-inhibitory and apoptosis-inducing effects in gastric cancer cells in vitro and in vivo.4) Moreover, studies have shown that paeonol prevents inflammatory diseases of the alimentary canal, such as irritable gastric ulcer, with minimal side effects.5) However, studies on the ethanol-induced gastric ulcer effect of paeonol are lacking. Currently, the listed paeonol dosages are administered via ordinary oral tablets and injection. However, paeonol has poor water solubility, easy oxidation, and a short biological half-life. [6][7][8] The paeonol products are unable to prolong effective drug concentration in blood to influence the oral bioavailability of a drug. Therefore, the present study, which is based on the properties of paeonol, has been designed to develop gastric retention tablets using modern technology to achieve prolonged presence in the stomach, thereby improving treatment of gastric ulcer. This approach has a profound clinical significance in developing a novel sustained-release delivery syst...

Mechanisms underlying gastroprotective effect of paeonol against indomethacin-induced ulcer in rats

“…The present study revealed gastroprotective influence of paeonol at both low and high doses that was mediated through its antioxidant, anti-inflammatory, and antiapoptotic effects. Paeonol ability to reduce the ulcer index was comparable to the reference drug, ranitidine, and in accordance with the gastroprotection reported by Zhang et al 13 Oxidative damage observed in the gastric mucosa of IND group was well explained by Maity et al 29 Paeonol ameliorated IND-induced lipid peroxidation in the gastric mucosa may be owed to its previously reported antioxidant property. 10,11,13 The current study shows that paeonol replenished GSH content, restored SOD activity, and increased HO-1 gene expression in the gastric mucosa.…”

“…9 These properties of paeonol offered the basis for its function as an organ protective agent in various disease models. [10][11][12] Despite that the role of paeonol in the gastrointestinal diseases was examined, 13 the mechanisms underlying its gastroprotective effect need to be clarified. The present study aimed at elucidating possible mechanisms underlying paeonol protective effect on gastric ulcer.…”