Oral Sustained Release Formulation Research Articles

Analysis of the Medication Persistence Rate for and Adherence to Oral 5-Aminosalicylic Acid Preparations in Japanese Patients with Ulcerative Colitis: Study Using a Nationwide Claims Database

Introduction: 5-aminosalicylic acid (5-ASA) is the first-line drug for the treatment of mild-to-moderate ulcerative colitis (UC). Three oral sustained-release formulations are often used. However, no unified view of their actual use in routine medical practice has been presented to date. Methods: Using a health insurance claims database, we extracted patients with an initial diagnosis of mild-to-moderate UC during the period from December 1, 2017, to March 31, 2022. For the three types of oral 5-ASA formulation, we calculated and compared descriptive statistics of medication persistence rates (MPR), proportions of days covered (PDC), and adherence proportion (PDC ≥80%) in the extracted population. Results: An oral 5-ASA formulation was used in combination with a topical preparation (cohort 1) in 899 patients, and oral 5-ASA was used alone (cohort 2) in 1,829 patients. In cohort 1, MPR at days 151–180 with concomitant use of topical formulation was significantly higher for the Multi Matrix System™ (MMX) formulation (65.2%) compared with that for pH-dependent formulation (51.7%, p < 0.025), while MPR tended to be higher for MMX than for the time-dependent formulation (56.4%, not significant). During days 151–180 after starting the oral formulation, MPR for MMX (66.7% and 65.8%) was higher than for pH-dependent (55.9% and 55.3%) and time-dependent (57.6% and 55.9%) formulations in cohorts 1 + 2 and 2, respectively. In cohort 1, there was a significant difference between MMX (68.3%) and pH-dependent (57.1%) formulations, but no significant difference was seen with time-dependent formulations (61.8%). In terms of the proportion of adherence until day 180, MMX was significantly better than the other formulations. Conclusion: The analyses of the three oral 5-ASA formulations suggested that both MPR and medication adherence were better for the MMX formulation than for time-dependent or pH-dependent formulations.

Floating Microspheres: An Overview

Abstract: This following review on Floating Microspheres is to highlight current literature and addition of newer approaches in floating microspheres as drug delivery system. Current studies show that floating microspheres can attain delayed and sustained release oral formulations with ability to achieve various release patterns, low dosage dumping risk, with repeatable and short gastric retention time.

Elucidation of Rate-determining Step in Dissolution Process of Oral Sustained-Release Formulations by Direct Observation

Elucidation of Rate-determining Step in Dissolution Process of Oral Sustained-Release Formulations by Direct Observation

Formulation and Evaluation of Mucoadhesive in-Situ Nasal Gel of Tapentadol Hydrochloride

Tapentadol Hydrochloride is a Tapentadol is a centrally acting analgesic. It has 33% bioavailability due to its first pass effect and hence possesses problems in the development of oral sustained release formulations. Mucoadhesive thermo reversible in-situ nasal gel of Tapentadol HCl was designed and developed to sustain its release due to the increased nasal residence time of the formulation. Poloxamer 407 (PF 127) was selected as it has excellent thermo sensitive gelling properties. HPMCK4M was added to impart mucoadhesive to the formulation, and PEG 400 was used to enhance the drug release. 32 Factorial designs were employed to assess the effect of concentration of HPMCK4M and PEG 400 on the performance of in-situ nasal gel systematically and to optimize the formulation. An optimized in-situ nasal gel was evaluated for appearance, pH, drug content, gelation temperature, mucoadhesive force, viscosity and ex-vivo permeability of drug through nasal mucosa of a goat. Additionally, this formulation was proved to be safe as histopathological studies revealed no deleterious effect on nasal mucosa of a goat after prolonged exposure of 21 days to the optimized formulation. Thus the release of Tapentadol Hydrochloride can be sustained if formulated in an in-situ nasal gel containing poloxamer 407 to achieve its prolonged action.

An in vivo pharmacokinetic study of metformin microparticles as an oral sustained release formulation in rabbits

BackgroundMetformin hydrochloride is a biguanide derivative that has been widely used to treat type 2 diabetes in humans. In veterinary medicine, metformin has shown increasing potential for diabetes treatment in different species, such as equids, dogs, cats and rabbits. It is highly hydrophilic, with incomplete gastrointestinal absorption and very large variability in absolute bioavailability between species, ranging from 4% in equids to 60% in humans. Metformin also shows a short half-life of approximately 2 h in dogs, cats, horses and humans. The objectives of this study were to evaluate a poly (lactic acid) (PLA) metformin microparticle formulation to test in rabbits and conduct a pharmacokinetics study of intravenous (SIV) and oral solution (SPO) metformin administration and oral PLA microparticle (SPLA) administration to rabbits to evaluate the improvement in the metformin pharmacokinetics profile.ResultsMetformin-loaded PLA microparticles were characterized by a spherical shape and high encapsulation efficiency. The results from Fourier transform infrared (FTIR) spectroscopy suggested the presence of interactions between metformin and PLA. X-Ray diffraction (XRD) analysis corroborated the results from the differential scanning calorimetry (DSC) studies, showing that metformin is present in an amorphous state within the microparticles. Physicochemical characterization suggested that PLA and metformin hydrochloride interacted within the microparticles via hydrogen bonding interactions. The pharmacokinetic study in rabbits showed sustained-release characteristics from the prepared microparticles with a delay in the time needed to reach the maximum concentration (Tmax), decreased Cmax and bioavailability, and increased mean residence time (MRT) and half-life compared to the pure drug solution.ConclusionsMetformin-loaded PLA microparticles showed optimal and beneficial properties in terms of their physicochemical characteristics, making them suitable for use in an in vivo pharmacokinetic study. The pharmacokinetic parameters of the metformin microparticles from the in vivo study showed a shorter Tmax, longer MRT and half-life, decreased Cmax and the prolonged/sustained release expected for metformin. However, the unexpected decrease in bioavailability of metformin from the microparticles with respect to the oral solution should be evaluated for microparticle and dose design in future works, especially before being tested in other animal species in veterinary medicine.

Comparison of Pharmacokinetic Profiles of Beraprost Sustained Release in Japanese, Chinese, and Korean Healthy Adult Males.

Beraprost sodium (BPS), an orally administrable prostaglandin I2 derivative, is used for the treatment of chronic arterial occlusion and pulmonary arterial hypertension and has potential efficacy in nephropathy. Beraprost sustained release (beraprost SR) is an oral sustained-release formulation of BPS. To confirm the dose rationale reported in a multi-regional study of nephropathy patients in Asia, this open-label study evaluated ethnic differences in the pharmacokinetic profiles of BPS and its active diastereomer (BPS-314d) after beraprost SR administration among healthy Japanese, Chinese, and Korean adult males. Twelve healthy subjects in each ethnic group were enrolled. Subjects received a single oral dose of 120μg beraprost SR under fasting conditions. The geometric mean ratio (90% confidence interval) of the maximum plasma concentration (Cmax) and area under the plasma concentration-time curve from time 0 to time of the last quantifiable concentration (AUClast) of BPS was 1.12 (0.85-1.48) and 1.40 (1.05-1.86) in Chinese, and 1.18 (0.90-1.55) and 1.18 (0.89-1.58) in Korean compared to Japanese subjects. These differences were not clinically relevant. Similarly, differences in the Cmax and AUClast of BPS-314d were also small among the ethnic groups. Urinary excretion of BPS and BPS-314d was limited in all ethnic groups. Together, these findings indicate that the pharmacokinetics of beraprost SR are not affected by ethnic background. There were no clinically meaningful ethnic differences in the pharmacokinetics of BPS and BPS-314d following beraprost SR administration among Japanese, Chinese and Korean populations.

Quality by Design (QbD) driven Systematic Development of Nano-lipoidal Carrier of Poorly Water Soluble Anti-tubercular agent-Rifabutin.

ABSTRACT In the present research work, Rifabutin, drug used for tuberculosis infection, was encapsulated in lipidic nanoparticles with a view to develop a sustained release oral formulation. The nanocarrier loaded rifabutin, prepared by the solvent diffusion evaporation method and evaluated for its physical (nanoparticles size distribution) and chemical (drug content) stability. To optimize the identified independent variables, Box-Behnken Design (BBD) was utilized effectively. The result showed that a size of optimized formulation was found to be 315 ± 10.96 nm and PDI of 0.310 ± 0.05; the encapsulation efficiency was found to be (66.3 ± 3.85). On encapsulation, the nanocarrier showed amorphous pattern of drug studied using X-ray Diffractometric analysis. The release pattern of rifabutin loaded nanocarrier revealed that it represents the sustained release kinetics in comparison to plain drug. Thus, nanotechnology-based formulation may reduce frequency, provide medications more efficaciously, ultimately reducing patient avoidance.

Microminipig: A suitable animal model to estimate oral absorption of sustained-release formulation in humans.

We investigated the gastrointestinal absorption characteristics of oral sustained-release formulations in microminipigs, dogs, and monkeys in order to clarify the similarities in absorption properties between these animals and humans. Time profiles of oral absorption of nifedipine and valproic acid were calculated from the plasma concentration-time profiles of the drugs by a deconvolution method. The curves for both drugs in microminipigs were close to or slightly higher than those in humans, whereas those in monkeys were lower. Furthermore, the plasma concentration-time profiles of the drugs were subjected to non-compartmental analysis. The fractions of a dose absorbed into the portal vein (FaFg) in microminipigs ranged from 50 to 100% of the human values, whereas those in monkeys were less than half the human values. In addition, the other absorption-related parameters for the sustained-release formulation in microminipigs, as well as monkeys, were comparable to those in humans. In conclusion, the oral absorption properties of microminipigs and humans were similar regarding the sustained-release formulations. Therefore, microminipig is a suitable animal model to estimate the oral absorption of sustained-release formulations in humans.

Alginate Microspheres: The Innovative Approaches to Production of the Microbeads/Micro-Particles

Multiparticulate dosage form is pharmaceutical formulations where the active substance is in the form of a number of small independent subunit such as, granules, microparticle, beads, and microspheres. Multiparticulate drug delivery systems are specifically suitable for achieving delayed and sustained release oral formulations with a minimum risk of dose dumping, local irritation, systemic toxicity, and variation in rate of bioavailability as they are less dependent on gastrointestinal transit time and offers many advantages over unit particulate dosage forms. Microbeads are small, sphere shaped, systematically produced free-flowing properties, semi-spherical solid units. Microbeads are the agglomerates of about size ranging from 0.5 mm to 1.0 mm, obtained from various starting materials and utilizing different innovative techniques. A blend of multiparticulate can also be used to provide the desired drug release profile. These round shaped particles produced by mostly principle of atomization technique.Among various different innovative techniques Vibration technology, Electrostatic bead generator, Jetcutter technology, electrostatic forces, dropping method and a mechanical cutting device are few of many. In current article it describes about the total methods involved and their working principles with diagrams were clearly illustrated. Now a days sodium alginate beads were designed by these technologies mostly in relative to microencapsulation techniques.&#x0D; Keywords: Atomization, Vibrating technology, Jetcutter device, Electrostatic bead generator Dropping method and electro-spray technology

Silk Fibroin as a Novel Alcohol-Resistant Excipient for Sustained-Release Tablet Formulation.

Concomitant intake of alcoholic beverages with sustained-release oral formulations may potentially lead to dose dumping. Alcohol-resistance testing is currently a requirement for the manufacturers by regulatory authorities. Silk fibroin produced by silkworm Bombyx mori is suggested in this work as a potential alternative to a narrow spectrum of alcohol-resistant excipients. Oxycodone HCl, tramadol HCl, and flurbiprofen were selected as model drugs and formulated with regenerated silk fibroin either in the form of an amorphous solid dispersion or as a physical mixture and compressed into tablets. Preliminary compactability and tampering-resistance studies were performed. The ethanol-resistance was tested in media containing 5%, 10%, 20%, or 40% (v/v) ethanol concentration. Drug release profiles were compared using f2 similarity factor. Good mechanical tampering-resistance (tensile strength of 14.6MPa at 400MPa compression pressure) was obtained for tablets compressed from physical mixture. Tablets compressed from amorphous solid dispersion had lower tensile strength (2.2MPa) but showed chemical tampering-resistance to extraction by pure ethanol (7.1% of oxycodone HCl after 24h). Drug release is controlled predominantly by swelling and diffusion. With an increasing ethanol concentration in release medium, the tablets swelled less, resulting in a slower release. This trend was similar for all tested drugs and for both physical states formulations. No dose dumping occurred in the presence of ethanol; therefore, silk fibroin could be considered as an alternative alcohol-resistant excipient for sustained release application.

Exploitation of enrofloxacin-loaded docosanoic acid solid lipid nanoparticle suspension as oral and intramuscular sustained release formulations for pig

In our previous study, enrofloxacin-loaded docosanoic acid solid lipid nanoparticles (SLNs) could be effectively delivered to cells in vitro. In this study, its properties and exploitation as possible oral and intramuscular sustained release formulations for pigs were studied after being made into suspension. The re-dispersed time and sedimentation rate of the nanosuspension were 55 s and 1, respectively. It showed good stability when stored away from light and sustained release in pH = 7.4 PBS buffer. The suspension exhibited no irritation at the injection site and good palatability. Compared with commercial injection and soluble powder, the nanosuspension increased the bioavailability of enrofloxacin by 1.63 and 2.38 folds, and extended the mean residence time (MRT) of the drug from 11.27 and 12.33 to 37.76 and 35.15 h after intragastric and intramuscular administration, respectively. These results suggest that docosanoic acid SLN suspension (DAS) might be a promising oral and intramuscular sustained release formulation to enhance the pharmacological activity of enrofloxacin.

Development and in vitro characterization of chitosan-coated polymeric nanoparticles for oral delivery and sustained release of the immunosuppressant drug mycophenolate mofetil

Objective: To develop an oral sustained release formulation of mycophenolate mofetil (MMF) for once-daily dosing, using chitosan-coated polylactic acid (PLA) or poly(lactic-co-glycolic) acid (PLGA) nanoparticles. The role of polymer molecular weight (MW) and drug to polymer ratio in encapsulation efficiency (EE) and release from the nanoparticles was explored in vitro.Methods: Nanoparticles were prepared by a single emulsion solvent evaporation method where MMF was encapsulated with PLGA or PLA at various polymer MW and drug: polymer ratios. Subsequently, chitosan was added to create coated cationic particles, also at several chitosan MW grades and drug: polymer ratios. All the formulations were evaluated for mean diameter and polydispersity, EE as well as in vitro drug release. Differential scanning calorimetry (DSC), surface morphology, and in vitro mucin binding of the nanoparticles were performed for further characterization.Results: Two lead formulations comprise MMF: high MW, PLA: medium MW chitosan 1:7:7 (w/w/w), and MMF: high MW, PLGA: high MW chitosan 1:7:7 (w/w/w), which had high EE (94.34% and 75.44%, respectively) and sustained drug release over 12 h with a minimal burst phase. DSC experiments revealed an amorphous form of MMF in the nanoparticle formulations. The surface morphology of the MMF NP showed spherical nanoparticles with minimal visible porosity. The potential for mucoadhesiveness was assessed by changes in zeta potential after incubation of the nanoparticles in mucin.Conclusion: Two chitosan-coated nanoparticles formulations of MMF had high EE and a desirable sustained drug release profile in the effort to design a once-daily dosage form for MMF.

Chlorambucil loaded in mesoporous polymeric microspheres as oral sustained release formulations with enhanced hydrolytic stability

Chlorambucil, a chemotherapeutic agent, is usually administered orally to treat chronic lymphocytic leukemia and some other types of cancers in regimens of conventional and metronomic chemotherapies. However, the hydrolytic instability of chlorambucil is a major limitation in achieving the optimum therapeutic performance. In this work, mesoporous polymeric microspheres were prepared by free radical suspension copolymerization of methyl acrylate and divinylbenzene in the presence of porogen. Chlorambucil was loaded into the mesoporous polymeric microspheres through adsorption of the drug in aqueous media with high loading capacity up to more than 350 mg/g. Chlorambucil-loaded mesoporous polymeric microspheres showed sustained release property in media simulating gastrointestinal fluids, with nearly zero order release kinetics. Furthermore, the mesoporous polymeric microspheres as carriers greatly stabilized chlorambucil against its hydrolysis. The hydrolyzation percentage of chlorambucil that was adsorbed on the microspheres after incubation for 36 h in media simulating gastrointestinal fluids was less than 10%, while more than 90% of free chlorambucil hydrolyzed after incubation in the same media for 4 h. The chlorambucil-loaded mesoporous polymeric microspheres may be used as oral sustained release formulations, especially as oral formulations for the application in metronomic chemotherapy.

Preparation and In vitro Evaluation of Enteric Coated Oral Vancomycin Hydrochloride Sustained Release Formulation with Mucoadhesive Properties

Clostridium difficile is a species of gram-positive bacteria thought to infect patients with weakened immune response resulting in colitis. Oral vancomycin hydrochloride is given four times a day to treat Clostridium difficile colitis and is commercially available in the form of capsule and solution. Patient’s compliance is the main issue in this treatment due to the multiple dosing frequencies. Accordingly, replacement of such dose regimen with a once daily dosage will enhance patient compliance. In this study, mucoadhesive vancomycin hydrochloride tablets were prepared with the use of chitosan to exert a local effect in the colon. Sustained release property was also imparted by chitosan. Enteric coating with Eudragit® S 100 was applied to prevent the sticking of chitosan tablets in the stomach and small intestine and deliver the tablets intact to the colon. The prepared tablets were evaluated for In vitro drug release for 24 hours and compared with the marketed formulation. The formulation was found to release in a sustained manner in pH 7.4 buffer allowing the colon delivered oral vancomycin hydrochloride to be a promising formulation in the development of a once daily treatment for Clostridium difficile colitis.

FORMULATION, EVALUATION AND OPTIMIZATION OF RANITIDINE HYDROCHLORIDE FLOATING TABLETS WITH IMPROVED GI ABSORPTION

Oral drug delivery system represents one of the main areas of sustained drug delivery system. Floating drug delivery system related to oral sustained drug delivery system group, which is capable of floating in the stomach for an exteneded period of time. Ranitidine hydrochloride is a histamine H2-receptor antagonist. It is widely prescribed in active duodenal ulcers, gastric ulcers, Zollinger-Ellison syndrome and GERD. A traditional oral sustained release formulation releases most of the drug at the colon, thus the drug should have absorption window either in the colon or throughout the gastrointestinal tract. Ranitidine is absorbed only in the initial part of the small intestine and has 50% absolute bioavailability. The aim of the present research is to provide a gastroretentive system for sustained release of Ranitidine hydrochloride in the upper part of the gastrointestinal tract in the form of floating tablet. Gastroretentive tablets of Ranitidine Hydrochloride were prepared by direct compression technique using polymers like Carbopol, Chitosan, Styrene-divinylbenzene and the mixture of Magnesium stearate as a lubricant, Talc as a glidant and Lactose as fillers. The results of the present research show that the chitosan and carbopol 940 mixed matrices can be used to modify release rates in hydrophilic matrix tablets prepared by direct compression. Incorporation of the highly porous low-density copolymer in the matrix tablets provides densities that are lower than the density of the release medium. 17% w/w low density copolymer (based on the mass of the tablet) was sufficient to achieve proper in vitro floating behavior for at least 8 h. Keywords: Floating drug delivery system, Ranitidine hydrochloride, Gastrointestinal tract, Carbopol, ChitosanÂ

STATISTICAL EXPERIMENTAL DESIGN FOR PHARMACEUTICAL DEVELOPMENT OF SUSTAINED RELEASE REGIMEN OF LINEZOLID WITH PREDICTABLE DESIGN SPACE

The objective of this investigation was to develop an oral sustained release formulation of linezolid that would maximize the duration of active drug concentration in the extracellular fluid, thus assuring the therapeutic efficacy. This rationale was based on the observation that the an efficacy of linezolid depends mainly on the length of time that bacteria are exposed to antibiotic concentrations above the minimum inhibitory concentration (T&gt;MIC). linezolid sustained release tablets were prepared by wet granulation method. A full factorial design for two-factor three levels was employed systematically to optimize drug release profile at 1, 4, 8 and 16 h. Film-coated sustained release matrix tablet exhibited fickian diffusion drug release kinetics approaching Higuchi model. The significance of the results was analyzed using analysis of non-variance (ANOVA) and P MIC for at least 24 hours.

Abstract 1620: Oral IL-10 suppresses colon carcinogenesis via elimination of pathogenic CD4+ T-cells and induction of antitumor CD8+ T-cell activity

Abstract An oral sustained-release formulation of Interleukin-10 suppressed tumor growth and enhanced survival in the APCmin/+ / Bacteroides fragilis spontaneous colon cancer model. Therapeutic benefit was associated with a 5-fold reduction in CD4+RORγt+Foxp3-IL-17+ T-helper cell, CD4+RORγt+Foxp3+IL-17+ pathogenic T-regulatory cell (pgTreg) and CD4+RORγt-Foxp3+IL-17- conventional T-regulatory cell (cTreg) numbers; and a concurrent enhancement of CD8+ T-cell cytotoxicity in the colonic lamina propria. Selective subset depletion and functional blockade studies demonstrated that CD4+RORγt+IL-17+ T-cell subsets and CD4+Foxp3+ cTreg supported tumorigenesis/tumor progression whereas CD8+ cytotoxic T-lymphocytes suppressed tumor growth. These findings establish the utility of oral particulate IL-10 as a potential new therapeutic in the management of colon cancer and shed light on the cellular mechanisms that underlie its antitumor activity. Note: This abstract was not presented at the meeting. Citation Format: TAO GU, Magdia DeJesus, Thomas P. Burris, Nejat K. Egilmez. Oral IL-10 suppresses colon carcinogenesis via elimination of pathogenic CD4+ T-cells and induction of antitumor CD8+ T-cell activity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1620. doi:10.1158/1538-7445.AM2017-1620

Oral IL-10 suppresses colon carcinogenesis via elimination of pathogenicCD4+ T-cells and induction of antitumor CD8+ T-cell activity

ABSTRACT An oral sustained-release formulation of Interleukin-10 suppressed tumor growth and enhanced survival in the APCmin/+/Bacteroides fragilis spontaneous colon cancer model. Therapeutic benefit was associated with a 5-fold reduction in CD4+RORγt+Foxp3−IL-17+ T-helper cell, CD4+RORγt+Foxp3+IL-17+ pathogenic T-regulatory cell and CD4+RORγt−Foxp3+IL-17− conventional T-regulatory cell numbers and a concurrent 2-fold enhancement in CD8+ T-cell activity in the colon. Selective subset depletion and functional blockade studies demonstrated that at steady-state CD4+RORγt+IL-17+ T-cell subsets and CD4+Foxp3+ cTreg supported tumorigenesis, whereas CD8+ cytotoxic T-lymphocytes impeded tumor progression following IL-10 therapy. Suppression of tumor growth by CD8+ T-cells was associated with enhanced tumor infiltration and cytotoxic granule exocytosis. These findings establish the utility of oral IL-10 as a potential new therapeutic in the management of colon cancer and shed light on the cellular mechanisms that underlie its antitumor activity.

Methotrexate-loaded porous polymeric adsorbents as oral sustained release formulations

Methotrexate as a model drug with poor aqueous solubility was adsorbed into porous polymeric adsorbents, which was used as oral sustained release formulations. In vitro release assay in simulated gastrointestinal fluids showed that the methotrexate-loaded adsorbents showed distinct sustained release performance. The release rate increased with increase in pore size of the adsorbents. In vivo pharmacokinetic study showed that the maximal plasma methotrexate concentrations after oral administration of free methotrexate and methotrexate-loaded DA201-H (a commercial porous polymeric adsorbent) to rats occurred at 40min and 5h post-dose, respectively; and the plasma concentrations decreased to 22% after 5h for free methotrexate and 44% after 24h for methotrexate-loaded DA201-H, respectively. The load of methotrexate into the porous polymeric adsorbents not only resulted in obvious sustained release, but also enhanced the oral bioavailability of methotrexate. The areas under the curve, AUC0–24 and AUC0-inf, for methotrexate-loaded DA201-H increased 3.3 and 7.7 times, respectively, compared to those for free methotrexate.

Pharmacokinetic analysis of modified-release metoprolol formulations: An interspecies comparison

In the current study, we investigated the metoprolol absorption kinetics of an in-house produced oral sustained-release formulation, matrices manufactured via prilling, and two commercially available formulations, ZOK-ZID® (reservoir) and Slow-Lopresor® (matrix) in both New Zealand White rabbits and Beagle dogs, using a population pharmacokinetic analysis approach.The aim of this study was to compare the in vivo pharmacokinetic (PK) profiles of different formulations based on metoprolol, a selective adrenergic β1-receptor antagonist, in dogs and rabbits and to contrast the observed differences. To that end, metoprolol (50 to 200mg) was administered to 6 Beagle dogs and 6 New Zealand White rabbits as a single intravenous (IV) bolus injection and to 8 dogs and 6 rabbits as an oral modified release formulation. To derive pharmacokinetic parameters from the data, a non-linear mixed-effects model was developed using NONMEM® where the contribution of observations below the limit of detection (BDL, below detection limit) to the parameter estimates was taken into account in the parameter estimation procedure.In both species and for the three modified release formulations, different absorption models were tested to describe the PK of metoprolol following oral dosing. In Beagle dogs, plasma concentration-time profiles were best described using a sequential zero- and first-order absorption model. In rabbits though, the absorption phase was best described using a first-order process only.In both species, the reservoir formulation ZOK-ZID® was behaving quite similarly. In contrast, the absorption properties of both matrix formulations were rather different between species. This study indicates that the PK of the reservoir formulation is similar in both species, even after accounting for the almost completely missed absorption phase in rabbits. The insights gained further illustrate that rabbits are not very well suited to study the PK of the current matrix formulations in view of their less optimal prolonged release characteristics and the resulting fast decline in metoprolol plasma levels.