Release Of Metoprolol Tartrate Research Articles

A superabsorbent and pH-responsive copolymer-hydrogel based on acemannan from Aloe vera (Aloe barbadensis M.): A smart material for drug delivery

Combining natural polysaccharides with synthetic materials improves their functional properties which are essential for designing sustained-release drug delivery systems. In this context, the Aloe vera leaf mucilage/hydrogel (ALH) was reacted with acrylic acid (AA) to synthesize a copolymerized hydrogel, i.e., ALH-grafted-Polyacrylic acid (ALH-g-PAA) through free radical copolymerization. Concentrations of the crosslinker N,N′-methylene-bis-acrylamide (MBA), and the initiator potassium persulfate (KPS) were optimized to study their effects on ALH-g-PAA swelling. The FTIR and solid-state NMR (CP/MAS 13C NMR) spectra witnessed the formation of ALH-g-PAA. Scanning electron microscopy (SEM) analysis revealed superporous nature of ALH-g-PAA. The gel fraction (%) of ALH-g-PAA was directly related to the concentrations of AA and MBA whereas the sol fraction was inversely related to the concentrations of AA and MBA. The porosity (%) of ALH-g-PAA directly depends on the concentration of AA and MBA. The ALH-g-PAA swelled admirably at pH 7.4 and insignificantly at pH 1.2. The ALH-g-PAA offered on/off switching properties at pH 7.4/1.2. The metoprolol tartrate was loaded on different formulations of ALH-g-PAA. The ALH-g-PAA showed pH, time, and swelling-dependent release of metoprolol tartrate (MT) for 24 h following the first-order kinetic and Korsmeyer-Peppas model. Haemocompatibility studies ascertained the non-thrombogenic and non-hemolytic behavior of ALH-g-PAA.

Controlled metoprolol tartrate release from poly(ε-caprolactone)-poly(ε-caprolactone)/polyethylene oxide/metoprolol tartrate composites with alternating multi-layered structures prepared through layer-multiplying co-extrusion

Multi-layered structure design has provided a promising and powerful strategy for the fabrication of controlled-release dosage forms. However, a convenient and effective preparation technology is still urgently needed. Herein, we applied layer-multiplying co-extrusion (LMCE) technology to construct poly(ε-caprolactone)-poly(ε-caprolactone)/polyethylene oxide/metoprolol tartrate (PCL-PCL/PEO/MPT) composites with alternating multi-layered structures in one step. The layer number could be doubled by an addition of layer-multiplying element. The degradation analysis indicated that fewer PCL layers were beneficial to the dissolution of PEO and increased the pore size in the matrix. The in vitro release results suggested the MPT encapsulated in PEO aggregates was released gradually in a layer-by-layer manner, and the MPT release was flexibly modulated by the number of PCL layer and PEO content. Additionally, methyl thiazolyl tetrazolium assay presented a potential application of PCL-PCL/PEO/MPT composites in tissue engineering. The LMCE technology should have great potential for the preparation of controlled-release dosage forms.

ВПЛИВ РОЗМІРУ ПОР ТА МОРФОЛОГІЇ МЕЗОПОРИСТОГО КРЕМНІЮ НА ВИВІЛЬНЕННЯ МЕТОПРОЛОЛУ ТАРТРАТУ

Purpose. Study pore size effect and morphology of mesoporous silica on metoprolol tartrate release.Methodology. A sample of hollow mesoporous silicon dioxide with amino-functional groups containing 12.7 wt. % metoprolol tartrate has been investigated as potential carriers for the controlled release of active substance. Studies of the release profiles of metoprolol tartrate were performed under the following conditions: dissolution medium was buffer solution with a pH of 7.4 (phosphate buffer); sampling time: from 0.5 h before 18 h. The metoprolol concentration in the liquid phase was evaluated by a UV-Vis spectrophotometer (Persee TU-190, Beijing, China) by use of quartz cuvettes with an optical path length of 1 cm at a maximum wavelength of 274 nm.Findings. In this work we have studied mesoporous silica as possible carrier to controlled release of metoprolol tartrate, a drug used in the treatment of some diseases of the cardiovascular system. The material for research was a sample of hollow mesoporous silicon dioxide with amino-functional groups 200–400 nm in size and 20–30 nm in shell thickness. A calibrated curve to determine the amount of metoprolol was constructed by determining the absorption dependence of the concentration of metoprolol in the range from 10 to 300 ppm. The same drug concentration was obtained as calculated from the drug release test formula, which concludes that the release of metoprolol is controlled.Originality. The controlled release of a sample of hollow spheres of mesoporous silicon dioxide filled with metoprolol tartrate was studied, which was synthesized by the School of Chemistry and Chemical Engineering, Qilu University of Technology, using a new technology, where hollow spheres of mesoporous silicon dioxide with amino groups were synthesized using CO2 gas bubbles as templates.Practical value. The metoprolol release amount could achieve a 50% release amounts within 1 hour and 90% within 5 hours, indicating that the synthesized mesoporous hollow sphere could achieve controlled drug release, and shows the potential of carriers with stimulus response and targeted therapy.

Design and Optimization of Bilayer Floating Gastroretentive Tablets of Metoprolol

Objectives: We aimed to formulate and optimize bilayer tablets of metoprolol tartrate consisting of both immediate and sustained release layer. Methods: A 23 factorial design was employed in formulating the GFDDS in which parameters, such as amount of HPMC (X1), sodium bicarbonate + citric acid (X2), and crospovidone (X3) were characterized as independent variables, whereas percent metoprolol release at 30 min (Y1), 4 hr (Y2), 8 hr (Y3), floating lag time (Y4), and total floating time (Y5) were considered as dependent variables. Findings: The formulations showed the biphasic release of metoprolol, where the immediate layer was completely disintegrated within 30 min and the release of the sustained layer was extended to 8 hr. Prompt disintegration of the immediate layer was facilitated by the combined effects of sodium starch glycolate and sodium bicarbonate + citric acid, whereas the extended release was assisted by HPMC. Formulations, where HPMC played the major role, were considered the best formulations. A good correlation was displayed between the experimental and predicted values that confirm the practicability of the model. Application/improvements: This study shows the effect of various variables in the release of metoprolol tartrate and formulates the bilayer tablets of metoprolol tartrate for the immediate and sustained drug release.Keywords: Metoprolol, Floating Drug Delivery System, Bilayer, Immediate Release Layer, Sustained Release Layer

Pore size effect on adsorption and release of metoprolol tartrate in mesoporous silica: Experimental and molecular simulation studies

Mesoporous silica nanoparticles (MSNs) have been widely studied as drug carriers to get sustained release behaviors, however, their application in sustained release of metoprolol tartrate (MPT) is limited. The possible reason is due to MPT molecule being bulky, while normal type MSNs like MCM-41 and SBA-15 have pore sizes of only 3–6 nm. In this study, two MCF-26 type MSNs were prepared with pore size of 11 or 15 nm, and used to conduct MPT release in comparison with MCM-41 and SBA-15. Both molecular simulation and MPT release experiments were performed to identify the pore size effect on adsorption and diffusion (release) of MPT in these MSNs. Finally, a kind of pH-sensitive MPT drug delivery system was obtained by coating the chosen MCF-26@MPT with an enteric polymer, which might find promising application in treating morning hypertension attack by orally administrating the drug delivery system before bedtime.

Design and Characterization of PVA–Methacrylic Acid Based Smart Polymeric System for Controlled Release of Metoprolol

In the present work covalently crosslinked smart polymeric system of hydrogel based on poly vinyl alcohol (PVA) and methacrylic acid (MA) was designed by free radical polymerization with different compositions using glyoxal (40 % water solution) as crosslinker. It was observed that swelling of hydrogel had a pronounced enhancing effect on increasing the concentration of MA due to availability of more ionized carboxylic groups of MA but produced an opposite effect on increasing the concentration of glyoxal owing to less porous structure. As far as PVA is concerned, swelling did not show significant effect on increasing the concentration of PVA. Hydrophilic polymer PVA rich in hydroxyl group pertained to be highly interactive with water. It was examined that the release of metoprolol tartrate decreased with increased concentration of glyoxal, but increased with increase in concentration of MA. PVA/MA hydrogel was characterized by Fourier transform infrared spectroscopy and X-ray diffraction to study the structure and crystallinity of hydrogel respectively. Morphology was studied through scanning electron microscopy. Furthermore differential scanning calorimetry and thermogravimetric analysis were also performed to characterize thermal stability. It may be concluded that the mechanism of drug release was mainly non-Fickian diffusion.

Formulation and evaluation of controlled release ethylcellulose and polyethylene glycol microspheres containing metoprolol tartrate.

Metoprolol tartrate is rapidly absorbed from both gastric and intestinal regions, after oral administration. To retard the release rate of the metoprolol tartrate, microspheres were prepared with varying concentrations of a mixture containing ethylcellulose and polyethylene glycol-6000. The prepared microspheres were evaluated for various physicochemical characteristics and in vitro drug release. The percent yield of microspheres was in the range of 75.2-87.3%. The particle size of microspheres was found to be in the range of 73.2-85.5μm. Fourier transform-infrared spectral analysis and differential scanning calorimetry concluded the absence of any interaction between the drug and the carriers. The release time profile of metoprolol tartrate from microspheres in 0.1N hydrochloric acid solution was to the extent of 33.4-60.2%. The complete release of metoprolol tartrate occurred from MPT-3 and MPT-4 in phosphate buffer solution (pH 7.4) within 8 and 7h, respectively, whereas the incomplete release (72.3%) occurred from MPT-1. Nearly, the complete release (98.5%) of metoprolol occurred from MPT-2 in 10h. Formulation MPT-2 would be a preferred formulation. The release of metoprolol involves diffusion rate limited (R2 = 0.9865) as a mechanism from drug release. The prepared microspheres of metoprolol tartrate eliminate the need for multiple dosing and provide patient compliance.

Comparison of metoprolol tartrate multiple-unit lipid matrix systems produced by different technologies

The aim of this study was to develop, evaluate and compare extended release mini-matrices based on metoprolol tartrate (MPT) and either glyceryl behenate (GB) or glyceryl palmitostearate (GPS). Mini-matrices were produced by three different techniques: hot melt extrusion, compression of melt granulates and prilling. Hot-melt extrusion and compression of granules obtained from melted material proved to be reliable, robust and reproducible techniques with aim of obtaining extended release matrices. Prilling tended to be susceptible to increased melt viscosity. Direct compression was not applicable for mini-matrix production due to poor powder flow. In general MPT release from all matrices was affected by its loading and the size of the units/particles. Processing of GB–MPT mixtures by different techniques did not lead to different drug release rates and patterns, while in case of GPS differently obtained matrices provided diverse MPT release outcomes. Matrices based on GB tended to have higher porosity compared to ones composed of GPS and thus most of the GB-based formulations showed faster drug delivery. FT-IR analysis revealed no interactions between primary components used for matrix production and Raman mapping outlined uniform MPT distribution throughout the units. DSC and X-ray studies revealed significant changes in the crystallinity of glycerides after storage under room conditions (GPS samples) and at increased temperature (GB and GPS samples), which was correlated to the changes seen in drug release rate and pattern after storage. Media composition in general tended to insignificantly affect GB matrices, while in case of GPS matrices increasing the pH and presence of biorelevant compounds induced faster drug release.

Investigation into the Effect of Ethylcellulose Viscosity Variation on the Drug Release of Metoprolol Tartrate and Acetaminophen Extended Release Multiparticulates-Part I.

Ethylcellulose is one of the most commonly used polymers to develop reservoir type extended release multiparticulate dosage forms. For multiparticulate extended release dosage forms, the drug release is typically governed by the properties of the barrier membrane coating. The ICH Pharmaceutical Development Guideline (ICH Q8) requires an understanding of the influence of critical material attributes and critical process parameters on the drug release of a pharmaceutical product. Using this understanding, it is possible to develop robust formulations with consistent drug release characteristics. Critical material attributes for ethylcellulose were evaluated, and polymer molecular weight variation (viscosity) was considered to be the most critical attribute that can impact drug release. To investigate the effect of viscosity variation within the manufacturer's specifications of ethylcellulose, extended release multiparticulate formulations of two model drugs, metoprolol tartrate and acetaminophen, were developed using ETHOCEL™ as the rate controlling polymer. Quality by Design (QbD) samples of ETHOCEL Std. 10, 20, and 100 Premium grades representing the low, medium, and high molecular weight (viscosity) material were organically coated onto drug layered multiparticulates to a 15% weight gain (WG). The drug release was found to be similar (f 2 > 50) for both metoprolol tartrate and acetaminophen multiparticulates at different coating weight gains of ethylcellulose, highlighting consistent and robust drug release performance. The use of ETHOCEL QbD samples also serves as a means to develop multiparticulate dosage formulations according to regulatory guidelines.

Calendering as a direct shaping tool for the continuous production of fixed-dose combination products via co-extrusion

In this study calendering is used as a downstream technique to shape monolithic co-extruded fixed-dose combination products in a continuous way. Co-extrudates with a metoprolol tartrate-loaded sustained-release core and a hydrochlorothiazide-loaded immediate-release coat were produced and immediately shaped into a monolithic drug delivery system via calendering, using chilled rolls with tablet-shaped cavities. In vitro metoprolol tartrate release from the ethylcellulose core of the calendered tablets was prolonged in comparison with the sustained release of a multiparticulate dosage form, prepared manually by cutting co-extrudates into mini-matrices. Analysis of the dosage forms using X-ray micro-computed tomography only detected small differences between the pore structure of the core of the calendered tablet and the mini-matrices. Diffusion path length was shown to be the main mechanism behind the release kinetics. Terahertz pulsed imaging visualized that adhesion between the core and coat of the calendered tablet was not complete and a gradient in coat thickness (varying from 200 to 600μm) was observed. Modulated differential scanning calorimetry and X-ray diffraction indicated that the solid-state properties of both drugs were not affected by the calendering procedure.

Thermoplastic polyurethanes for the manufacturing of highly dosed oral sustained release matrices via hot melt extrusion and injection molding

This study evaluated thermoplastic polyurethanes (TPUR) as matrix excipients for the production of oral solid dosage forms via hot melt extrusion (HME) in combination with injection molding (IM). We demonstrated that TPURs enable the production of solid dispersions – crystalline API in a crystalline carrier – at an extrusion temperature below the drug melting temperature (Tm) with a drug content up to 65% (wt.%). The release of metoprolol tartrate was controlled over 24h, whereas a complete release of diprophylline was only possible in combination with a drug release modifier: polyethylene glycol 4000 (PEG 4000) or Tween 80. No burst release nor a change in tablet size and geometry was detected for any of the formulations after dissolution testing. The total matrix porosity increased gradually upon drug release. Oral administration of TPUR did not affect the GI ecosystem (pH, bacterial count, short chain fatty acids), monitored via the Simulator of the Human Intestinal Microbial Ecosystem (SHIME). The high drug load (65wt.%) in combination with (in vitro and in vivo) controlled release capacity of the formulations, is noteworthy in the field of formulations produced via HME/IM.

Prilling as manufacturing technique for multiparticulate lipid/PEG fixed-dose combinations

This study focused on the evaluation of prilling as a technique for the manufacturing of multiparticulate dosage forms. Prills, providing controlled and immediate drug release, were processed and finally combined in capsules yielding a fixed-dose combination. Metoprolol tartrate (MPT) and hydrochlorothiazide (HCT) were used as controlled and immediate release model drugs, respectively. These drugs were embedded in matrices composed of fatty acids and polyethylene glycol (PEG). In order to tailor drug release from the prills, the type of fatty acid, the PEG molecular weight and the fatty acid/PEG ratio were varied. To provide controlled drug release, MPT was embedded in matrices containing PEG and behenic acid. Using different PEG molecular weights (PEG 4000, 6000 and 10,000), MPT release could be tailored over a wide range. To obtain immediate release, HCT was incorporated in matrices composed of PEG and stearic acid. Since high amounts (at least 60%) of PEG were needed for acceptable immediate release, HCT release was independent on PEG molecular weight. Solid state characterization revealed that MPT crystallinity was decreased, while HCT was molecularly dispersed throughout the matrix. Drug release of both MPT and HCT prills was stable during storage. Compared to a fixed-dose reference, oral co-administration of the MPT and HCT prills to dogs yielded a similar bioavailability for the HCT prills, while the MPT prills resulted in a significant higher bioavailability.

Evaluation of poly(2-ethyl-2-oxazoline) containing copolymer networks of varied composition as sustained metoprolol tartrate delivery systems.

Segmented copolymer networks (SCN) based on poly(2-ethyl-2-oxazoline) and containing 2-hydroxyethyl methacrylate, 2-hydroxypropyl acrylate, and/or methyl methacrylate segments have been evaluated as potential sustained release systems of the water soluble cardioselective β-blocker metoprolol tartrate. The structure and properties of the drug carriers were investigated by differential scanning calorimetry, attenuated total reflectance Fourier transform infrared spectroscopy, scanning electron microscopy, and atomic force microscopy. Swelling kinetics of SCNs in various media was followed, and the conditions for effective MT loading were specified. MT-loaded SCNs with drug content up to 80wt.% were produced. The release kinetics of metoprolol tartrate from the systems was studied and it was shown that the conetworks of different structure and composition are able to sustain the metoprolol tartrate release without additional excipients.

Pharmacokinetics and anti-hypertensive effect of metoprolol tartrate rectal delivery system

The main aim of this work was to develop rectal suppositories for better delivery of metoprolol tartrate (MT). The various bases used were fatty, water soluble and emulsion bases. The physical properties of the prepared suppositories were characterized such as weight variation, hardness, disintegration time, melting range and the drug content uniformity. The in vitro release of MT from the prepared suppositories was carried out. The evaluation of the pharmacological effects of MT on the blood pressure and heart rate of the healthy rabbits after the rectal administration compared to the oral tablets was studied. Moreover, the formulation with the highest in vitro release and the highest pharmacological effects would be selected for a further pharmacokinetics study compared to the oral tablets. The results revealed that the emulsion bases gave the highest rate of the drug release than the other bases used. The reduction effect of the emulsion MT suppository base on the blood pressure and heart rate was found to be faster and greater than that administered orally. The selected emulsion suppository base (F11) showed a significant increase in the AUC (1.88-fold) in rabbits as compared to the oral tablets. From the above results we can conclude that rectal route can serve as an efficient alternative route to the oral one for systemic delivery of MT which may be due to the avoidance of first-pass effect in the liver.

Development of hollow/porous floating beads of metoprolol for pulsatile drug delivery

The purpose of this work was to develop hollow calcium pectinate beads for floating pulsatile release of metoprolol tartrate intended for chronopharmacotherapy. Floating pulsatile concept was applied to increase the gastric residence of the dosage form having lag phase followed by a burst release. To overcome limitations of various approaches for imparting buoyancy, hollow/porous beads were prepared by simple process of acid-base reaction during ionotropic cross-linking using low methoxy pectin, xanthan gum, sodium carboxy methyl cellulose, guar gum, locust bean, gellan gum and calcium chloride as a cross-linking agent. Based on the preliminary studies optimized polymers were selected for formulation design with different polymers ratio concentrations. The obtained floating beads were studied for entrapment efficiency, buoyancy study, swelling index, surface morphology, in vitro release, stability studies and in vivo floating study. The floating beads obtained were porous, float up to 12-24h. The radiological studies (X-rays) pointed out the capability of the system to release drug in lower parts of GIT after a programmed lag time for hypertension. The floating beads provided expected two-phase release pattern with initial lag time during floating in acidic medium followed by rapid pulse release in phosphate buffer. From the accelerated stability studies, it was observed that the formulations are quite stable. All formulations followed first-order release kinetics by diffusion mechanism. This approach suggested the use of hollow calcium pectinate microparticles as promising floating pulsatile drug delivery system for site- and time-specific release of drugs acting as per chronotherapy of diseases.

Modulating Release of Metoprolol Tartrate with Nanostructured Silica Particles

To develop a kind of gastrointestinal timed-release preparation for Metoprolol Tartrate, nanostructured silica particles were chose for the purpose. Briefly, MCM-41 type mesoporous silica nanospheres with a size of 100-200 nm were synthesized through the reaction of tetraethyl orthosilicate (TEOS) in the water medium at 353 K, with introducing some cetyltrimethyl ammonium bromide (CTAB) as porogens. Various analytical methods, including FT-IR, XRD, TEM, N2 physisorption and thermal analysis, were applied to characterize the final products. Metoprolol Tartrate was then loaded into the mesoporous silica nanospheres by soaking. Results of the release of the drug in simulated gastric juice indicated that the drug can release up to 24 h and its maximum released amount was 4.5%. In the simulated intestinal juice the maximum cumulative released amount of metorprolol was 10.8%.In vitro release behavior revealed that the mesoporous silica were appropriate used as drug delivery system.

Hot-melt co-extrusion for the production of fixed-dose combination products with a controlled release ethylcellulose matrix core

In this study, hot-melt co-extrusion was evaluated as a technique for the production of fixed-dose combination products, using ethylcellulose as a core matrix former to control the release of metoprolol tartrate and a polyethylene oxide-based coat formulation to obtain immediate release of hydrochlorothiazide. By lowering the concentration of the hydrophilic additive polyethylene oxide in the plasticized ethylcellulose matrix or by lowering the drug load, the in vitro metoprolol tartrate release from the core was substantially sustained. The in vitro release of hydrochlorothiazide from the polyethylene oxide/polyethylene glycol coat was completed within 45 min for all formulations. Tensile testing of the core/coat mini-matrices revealed an adequate adhesion between the two layers. Raman mapping showed no migration of active substances. Solid state characterization indicated that the crystalline state of metoprolol tartrate was not affected by thermal processing via hot-melt extrusion, while hydrochlorothiazide was amorphous in the coat. These solid state characteristics were confirmed during the stability study. Considering the bioavailability of metoprolol tartrate after oral administration to dogs, the different co-extruded formulations offered a range of sustained release characteristics. Moreover, high metoprolol tartrate plasma concentrations were reached in dogs allowing the administered dose to be halved.

Prilling of fatty acids as a continuous process for the development of controlled release multiparticulate dosage forms

In this study, prilling was evaluated as a technique for the development of multiparticulate dosage forms using the fatty acids, stearic acid, and behenic acid as potential matrix formers to control the release of metoprolol tartrate (MPT), a highly water soluble drug. The in vitro drug release was dependent on the drug load, type of fatty acid, and pH of the dissolution medium. Higher drug loads resulted in faster release with behenic acid releasing drug over longer periods relative to stearic acid. The in vitro drug release was pH-dependent at low drug load with the release being slower at lower pH. Due to ionization of the fatty acid at pH 7.4, drug release was susceptible to the ionic strength at this pH value. Solid state characterization indicated that the crystalline state of the fatty acids was not affected by thermal processing via prilling, while the crystallinity of MPT was decreased. During storage, the amorphous MPT fraction recrystallized in the entire matrix. Drug release from behenic acid matrices was increased during storage at 40°C; however, no polymorphism of behenic acid was detected. The bioavailability of MPT, after oral administration to dogs as prills containing 30% and 40% MPT using behenic acid as matrix former, was not significantly different from a commercial sustained release reference formulation, although the 40% MPT prills showed a burst release.

Porous nanoparticles of metoprolol tartrate produced by spray-drying: development, characterization and in vitro evaluation

The present investigation was undertaken to fabricate porous nanoparticles of metoprolol tartrate by spray-drying using ammonium carbonate as pore former. Prepared nanoparticles were coated with Eudragit S100 polymer in order to prevent the release of metoprolol tartrate in the upper GI tract. It was shown that nanoparticles with low size ranges can be obtained with a low feed inlet rate. Micromeritic studies confirmed that nanoparticle batches are discrete and free flowing. Effects of the pore former on drug loading, porosity and in vitro release were studied. It was found that there was an increase in drug loading and porosity with increasing the amount of pore former. In vitro drug release studies showed that an increase in pore former made drug release faster. Release kinetics proved that nanoparticles follow a zero-order release mechanism.

Co-extrusion as manufacturing technique for fixed-dose combination mini-matrices

The aim of this study was to develop a multilayer (core/coat) dosage form via co-extrusion, the core providing sustained drug release and the coat immediate drug release. In this study polymers were selected which can be combined in a co-extruded dosage form. Several thermoplastic polymers were hot-melt extruded and evaluated for processability and macroscopic properties (surface smoothness, die swell). Metoprolol tartrate (MPT) and hydrochlorothiazide (HCT) were incorporated as sustained and immediate release model drugs, respectively. Based on the polymer screening experiments a combination of polycaprolactone (core) and polyethylene oxide (coat) was selected for co-extrusion trials, taking into account their drug release profiles and extrusion temperature (70°C). This combination (containing 10% HCT in the coat and 45% MPT in the core) was successfully co-extruded (diameter core: 3mm/thickness coat: 0.5mm). Adhesion between the two polymer layers was good. HCT release from the coat was complete within 30min, while MPT release was sustained over 24h (55%, 70%, 85% and 100% after 4, 8, 12 and 24h, respectively). DSC, XRD and Raman spectroscopy revealed that MPT remained crystalline during extrusion, whereas HCT was dissolved in the polyethylene oxide matrix. The in vivo study revealed no significant differences between the experimental formulation and the reference formulation (Zok-Zid® tablet). Fixed-dose combination mini-tablets with good in vitro and in vivo performance were successfully developed by means of co-extrusion, using a combination of polycaprolactone and polyethylene oxide.