Pharmacokinetic evaluation of a new oral sustained release dosage form of tramadol (original) (raw)
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Comparative bioequivalence studies of tramadol hydrochloride sustained-release 200 mg tablets
2010
Background: Tramadol hydrochloride is available as 50 mg immediate-release (IR) and 100 mg, 200 mg, and 300 mg sustained-release (SR) tablets. The recommended dose of tramadol is 50-100 mg IR tablets every 4-6 hours. The tramadol SR 200 mg tablet is a better therapeutic option, with a reduced frequency of dosing, and improved patient compliance and quality of life. The present study evaluated the bioequivalence of a generic tramadol SR 200 mg tablet. Methods: A comparative in vitro dissolution study was performed on the test and reference products, followed by two separate single-dose bioequivalence studies under fasting and fed conditions and one multiple-dose bioequivalence study under fasting conditions. These bioequivalence studies were conducted in healthy human subjects using an open-label, randomized, two-treatment, two-period, two-sequence, crossover design. The oral administration of the test and reference products was done on day 1 for both the single-dose studies and on days 1-5 for the multiple-dose study in each study period as per the randomization code. Serial blood samples were collected at predefined time points in all the studies. Analysis of plasma concentrations of tramadol and O-desmethyltramadol (the M 1 metabolite) was done by a validated liquid chromatography-mass spectrometry analytical method. The standard acceptance criterion of bioequivalence was applied on log-transformed pharmacokinetic parameters for tramadol and its M 1 metabolite. Results: The ratios for geometric least-square means and 90% confidence intervals were within the acceptance range of 80%-125% for log-transformed primary pharmacokinetic parameters for tramadol and its M 1 metabolite in all the three studies. Conclusion: The test product is bioequivalent to the reference product in terms of rate and extent of absorption, as evident from the single-dose and multiple-dose studies. Both the treatments were well tolerated.
The Veterinary Journal, 2009
The study evaluated the pharmacokinetics of tramadol and its major metabolites O-desmethyltramadol (M1), N-desmethyltramadol (M2) and N-O didesmethyltramadol (M5) following a single oral administration of a sustained release (SR) 100 mg tablet to dogs. Plasma tramadol concentration was greater than the limit of quantification (LOQ) in three dogs, M1 was quantified only in one dog while M2 and M5 were quantified in all of the dogs. The median values of C max (maximum plasma concentration), T max (time to maximum plasma concentration) and T 1/2 (half-life) for tramadol were 0.04 (0.17-0.02) lg mL À1 , 3 (4-2) and 1.88 (2.211-1.435) h, respectively. M5 showed median values of C max , T max and T 1/2 of 0.1 (0.19-0.09) lg mL À1 , 2 (3-1) and 4.230 (6.583-1.847) h, respectively. M2 showed median values of C max , T max and T 1/2 of 0.22 (0.330-0.080) lg mL À1 , 4 (7-3) and 4.487 (6.395-1.563) h, respectively. The findings suggest that the SR formulation of tramadol may not have suitable pharmacokinetic characteristics to be administered once-a-day as an effective and safe treatment for pain in the dog.
Veterinary Research Communications, 2009
The aim of the present paper was to test the oral administration of oral immediate release capsules of tramadol in dogs, to asses both its pharmacokinetic properties and its urine profile. After capsules administration of tramadol (4 mg/kg), involving eight male Beagle dogs, the concentration of tramadol and its main metabolites, M1, M2 and M5, were determined in plasma and urine using an HPLC method. The plasma concentrations of tramadol and metabolites were fitted on the basis of mono-and non-compartmental models, respectively. Tramadol was detected in plasma from 5 min up to 10 h in lesser amounts than M5 and M2, detected at similar concentrations, while M1 was detected in negligible amounts. In the urine, M5 and M1 showed the highest and smallest amount, respectively; M1 and M5 resulted widely conjugate with glucuronic acid. In conclusion, after oral administration of tramadol immediate release capsules, the absorption of the active ingredient was rapid, but its rapid metabolism quickly transformed the parental drug to high levels of M5 and M2, showing an extensive elimination via the kidney. Hence, in the dog, the oral immediate release pharmaceutical formulation of tramadol would have different pharmacokinetic behaviour than in humans.
Formulation , development , and evaluation of tramadol Hcl sustained-release dosage form
2018
Due to its side effect profile in comparison with other analgesics, tramadol Hcl may have a role in patients who are intolerant of conventional opioid and other non-opioid analgesics, those who have preexisting cardiopulmonary disease, such as the elderly or obese, and those in whom codeine use is inappropriate. In the acute and post-operative settings, it may have a place in multimodal, analgesia, where opioid and non-opioid drugs are given in combination to achieve analgesia, with a reduction in the incidence and severity of side effects.[1]
Clinical Drug Investigation, 2005
Abstract have been introduced in pain treatment in order to prolong the dosage interval to improve convenience for the patient. The objective of this study was to compare tramadol pharmacokinetics and intra-and intersubject variability after replicate single-dose administrations of a multiple-units SR formulation (capsule) and a single-unit formulation (tablet). Methods: This was a randomised, single-dose, single-centre study with an open-label, four-period, two-sequence, two-formulation, replicate crossover design in healthy subjects under fed conditions. The main outcome measures were the intra-and intersubject variance of the area under the concentration-time curve from 0 to 12 hours (AUC12) and maximum concentration (Cmax), as well as the mean AUC12 and Cmax for tramadol. Study drugs were a tramadol SR multiple-units formulation (capsule) and a tramadol SR single-unit formulation (tablet), each containing tramadol hydrochloride 100mg. The time interval from 0 to 12 hours of AUC12 of the single-dose design corresponds to the recommended twice-daily dosage interval for both study drugs during long-term treatment.
European Journal of Pharmaceutical Sciences, 2016
Tramadol hydrochloride is a centrally acting analgesic used for the treatment of moderate-to-severe pain. It has three main metabolites: O-desmethyltramadol (M1), N-desmethyltramadol (M2), and N,O-didesmethyltramadol (M5). Because of the frequent use of tramadol by patients and drug abusers, the ability to determine the parent drug and its metabolites in plasma and cerebrospinal fluid is of great importance. In the present study, a pharmacokinetic approach was applied using two groups of five male Wistar rats administered a 20 mg/kg dose of tramadol via intravenous (i.v.) or intraperitoneal (i.p.) routes. Plasma and CSF samples were collected at 5-360 min following tramadol administration. Our results demonstrate that the plasma values of C max (C 0 in i.v. group) and area under the curve (AUC) 0-t for tramadol were 23,314.40 ± 6944.85 vs. 3187.39 ± 760.25 ng/mL (C max) and 871.15 ± 165.98 vs. 414.04 ± 149.25 μg•min/mL in the i.v. and i.p. groups, respectively (p b 0.05). However, there were no significant differences between i.v. and i.p. plasma values for tramadol metabolites (p N 0.05). Tramadol rapidly penetrated the blood-brain barrier (BBB) and blood-cerebrospinal fluid barrier (BCSFB) (5.00 ± 0.00 vs. 10.00 ± 5.77 min in i.v. and i.p. groups, respectively). Tramadol and its metabolites (M1 and M2) were present to a lesser extent in the cerebrospinal fluid (CSF) than in the plasma. M5 hardly penetrated the CSF, owing to its high polarity. There was no significant difference between the AUC 0-t of tramadol in plasma (414.04 ± 149.25 μg•min/mL) and CSF (221.81 ± 83.02 μg•min/mL) in the i.p. group. In addition, the amounts of metabolites (M1 and M2) in the CSF showed no significant differences following both routes of administration. There were also no significant differences among the K p,uu,CSF(0-360) (0.51 ± 0.12 vs. 0.63 ± 0.04) and K p,uu,CSF(0-∞) (0.61 ± 0.10 vs. 0.62 ± 0.02) for i.v. and i.p. pathways, respectively (p N 0.05). Drug targeting efficiency (DTE) values of tramadol after i.p. injection were more than unity for all scheduled time points. Considering the main analgesic effect of M1, it is hypothesized that both routes of administration may produce the same amount of analgesia.
Pharmacokinetics and Pharmacodynamics Evaluation of Tramadol in Thermoreversible Gels
BioMed Research International
We evaluated pharmacokinetics (PK) and pharmacodynamics (PD) induced by new formulations of tramadol (TR) in thermoreversible gels. The poloxamer- (PL-) tramadol systems were prepared by direct dispersion of the drug in solutions with PL 407 and PL 188. The evaluated formulations were as follows: F1: TR 2% in aqueous solution and F2: PL 407 (20%) + PL 188 (10%) + TR 2%; F3: PL 407 (25%) + PL 188 (5%) + TR 2%; F4: PL 407 (20%) + TR 2%. New Zealand White rabbits were divided into four groups (n=6) and treated by subcutaneous route with F1, F2, F3, or F4 (10 μg·kg−1). PK evaluation used TR and M1 plasma levels. PD evaluation was performed with the measurement of both pupils’ diameters. F2 showed higher TR plasma concentration after 180 minutes and presented lower M1 concentrations at almost all evaluated periods. Areas under the curve (ASC0–480 and ASC0–∞) and clearance of F2 presented differences compared to F1. F2 presented significant correlation (Pearson correlation) between the en...
Review of extended-release formulations of Tramadol
2014
Abstract: Patients with chronic non-malignant pain report impairments of physical, social, and psychological well-being. The goal of pain management should include reducing pain and improving quality of life. Read this review and sign up to receive Journal of Pain Research here: http://www.dovepress.com/articles.php?article\_id=16193
International Journal of Pharmacy and Pharmaceutical Sciences, 2019
Objective: The objective of the present study was to develop "once daily" extended-release tablets of tramadol (100 mg) by wet granulation using hydrophilic polymer like hydroxypropyl methylcellulose K100M, K15M and polyethylene oxide (PEO). Methods: The tramadol matrix tablets were prepared by using different polymers like hydroxypropyl methyl cellulose (HPMC K15M and K100M), polyethylene oxide (PEO) as the nontoxic and easily available suitable matrix system. The extended-release tablets of tramadol (400 mg) were prepared wet granulation technique. Different pre-compression and post-compression were performed. In vitro dissolution tests were performed and percentage drug release was calculated. The Fourier-transform infrared spectroscopy (FTIR) studies conducted on pure drug tramadol and the optimized formulation (T6). Different release models like zero order, first order, higuchi and Korsemeyer-Peppas were applied to in vitro drug release data in order to evaluate the drug release mechanisms and kinetics. Results: Pre-compression and post-compression parameters satisfied with pharmacopeia specifications. The In vitro release studies were performed using USP type II apparatus showed that optimized formulation T6 consisting of polyethylene oxide (PEO) with 25 mg of the polymer was found to extended release of tramadol over a period of 24h. The optimized formulation T6 followed the zero-order kinetics as correlation coefficient (r 2 Conclusion: The present study shows that polyethylene oxide was found to play a great role in controlling release of tramadol from the matrix system. Accordingly, it can be concluded that the formulation is robust in the performance is less likely to be affected by the various factors studied.) values are higher than that of first-order release kinetics. In order to understand the complex mechanism of drug release from the optimized formulation T6 matrix system, the in vitro release rate were fitted to Korsemeyer-Peppas model and the release exponent value (n) obtained was 0.82105 exhibited anomalous (non fickian) diffusion mechanism.