Development, Physicochemical Characteristics and Pharmacokinetics of a New Sustained-Release Bilayer Tablet Formulation of Tramadol with an Immediate-Release Component for Twice-Daily Administration

Abstract

Background and objective: There are some potential concerns about the currently marketed solid oral dosage forms of tramadol, including decreased adherence to immediate-release (IR) formulations due to the high number of doses taken each day and the slow rise in the blood tramadol concentration after administration of sustained-release (SR) formulations, which may not achieve a rapid analgesic effect. To overcome these potential concerns, a twice-daily double-layered tablet formulation of tramadol comprising IR and SR layers was developed. This article reports studies that assessed its physicochemical and pharmacokinetic properties.

Methods: Dissolution tests of five bilayer tablet formulations (designated tablets A-E) and pharmacokinetic studies of tablets A and B were conducted to investigate the appropriate ratio of the IR/SR layers in the double-layered tablet. Additionally, pharmacokinetic studies of three finished dosage formulations (tablets C-E) were performed in healthy adult males to investigate the effect of food intake on drug absorption.

Results: Adjusting the excipients and tramadol content in the IR and SR layers of tablets A-E altered their dissolution profiles in a manner that could be predicted based on their compositions. The IR layer was released within 15 min, and the SR layer was slowly released over 10 h. In the pharmacokinetic study, the time to maximum plasma concentration (t_max) of tramadol after administration of tablets A (IR:SR: 20:80 mg) and B (40:60 mg) was shorter than that of a commercially available SR tablet, and the half-life (t_1/2) was longer than that of a commercially available IR tablet. For tablets C-E, administration after food did not affect the area under the concentration-time curve (AUC) or maximum drug concentration (C_max) of tramadol, but the t_max was prolonged by about 1 h compared with administration in fasting conditions. The mean ± standard deviation t_max and t_1/2 for tablet D (IR:SR: 35:65 mg) in the fasting condition was 1.09 ± 0.56 h and 7.82 ± 0.85 h, respectively. The respective values in the fed condition were 2.47 ± 1.06 h and 7.12 ± 0.85 h, respectively.

Conclusions: To address the potential concerns regarding existing formulations of tramadol, a twice-daily, extended-release bilayer formulation of tramadol consisting of an IR and SR layer was developed. Pharmacokinetic studies confirmed that the plasma tramadol concentration increased quickly after administration and was maintained over a long period of time.

Fig. 1

Schematic representation of the double-layer sustained-release tramadol tablet

Fig. 2

In vitro dissolution profiles of various prototype tablet formulations (designated X, Y and Z) using different ratios of HPC-H, CVP and CMC-Na as the matrix base and of a reference formulation (ZSR). Paddle speed: 50 rpm. Samples were collected at 0, 15 min, 30 min, 1 h, 2 h, 3 h, 4 h, 6 h and 8 h. CMC-Na carmellose sodium, CVP carboxyvinyl polymer, HPC-H hydroxypropyl cellulose-H, ZSR Zydol^® sustained-release tablet

Fig. 3

Comparative in vitro dissolution profiles of tablets A and B and two reference formulations in the Japanese Pharmacopoeia [15] dissolution test (pH 6.8) with paddle stirring at 50 rpm (n = 3). Paddle speed: 50 rpm. Samples were collected at 0, 15 min, 30 min, 1 h, 2 h, 3 h, 4 h, 6 h and 8 h. ZIR Zydol^® immediate-release tablet, ZSR Zydol^® sustained-release tablet

Fig. 4

Dissolution of the double-layered tablet (tablet C) in water. Photographs were taken at the start of stirring (a), after 4 min (the IR layer of the tablet quickly disintegrated and dissolved; b) and after 8 min (the IR layer had disappeared, and gelation of the SR layer was initiated on the surface; c)

Fig. 5

Mean plasma tramadol (a) and tramadol metabolite M1 (b) concentrations versus time profiles after a single oral dose of tablets A and B or two reference products in healthy male volunteers under fasting conditions. Values are means ± standard deviation (n = 11–12). IR immediate release, SR sustained release, ZIR Zydol^® IR tablet, ZSR Zydol^® SR tablet

Fig. 6

a Dissolution profiles of the finished dosage formulations (tablets C–E) and three commercially available products in the second fluid (pH 6.8). b Dissolution profiles of tablet D and commercially available bilayer sustained-release tramadol tablets (TZ100). Values in (a) and (b) are means ± standard deviation (n = 6). Paddle speed: 50 rpm. Samples were collected at 0, 5 min, 10 min, 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h and 10 h. IR25 Tramal^® OD tablet 25 mg, IR50 Tramal^® OD tablet 50 mg, SR100 Onetram^® QD tablet 100 mg, TZ100 Tramadol Sandoz^® sustained-release 100 mg bilayer tablet

Fig. 7

Comparison of the amount of tramadol released from tablet C after 15 min, 2 h and 10 h in various test conditions. (1) Paddle, 50 rpm, diluted McIlvaine buffer solution (pH 7.5). (2) Paddle, 100 rpm, diluted McIlvaine buffer solution (pH 7.5). (3) Paddle, 200 rpm, diluted McIlvaine buffer solution (pH 7.5). (4) Paddle, 50 rpm, diluted McIlvaine buffer solution (pH 7.5) + 1% polysorbate 80. (5) Paddle, 50 rpm, first fluid for dissolution test (pH 1.2). (6) Paddle, 50 rpm, second fluid for dissolution test (pH 6.8). (7) Paddle, 50 rpm, water. (8) Basket, 200 rpm, diluted McIlvaine buffer solution (pH 7.5). (9) Disintegration apparatus, diluted McIlvaine buffer solution (pH 7.5). Values are means ± standard deviation (n = 6)

Fig. 8

Mean plasma tramadol (a) and tramadol metabolite M1 (b) concentrations versus time profiles after a single oral dose of tablet D to healthy male volunteers under fasting and fed conditions. Values are means ± standard deviation (n = 19)

Fig. 9

Simulated plasma tramadol concentration during multiple oral doses of tablet D under fasting conditions. The graph also shows the trough values for tramadol concentrations obtained in a multiple-dose study using 100 mg tramadol tablets with a dissolution profile equivalent to tablet D [17, 18]