ethyl-cellulose and isosorbide-5-mononitrate

The aim of the present study was to develop the novel immediate-controlled release (ICR) tablets of isosorbide-5-mononitrate (5-ISMN) composed of an osmotic pump tablet core coated with an immediate-release layer. The novel ICR tablets of 5-ISMN could release drug quickly and continuously through a semi-permeable membrane (SPM) composed of ethylcellulose (EC)/polyethylene glycol (PEG) 4000 and cellulose acetate (CA)/PEG4000. Release tended to decrease with storage time. However, the drug release rates changed little for the SPM composed of EC/PVP K30. The weight loss test also confirmed these results. The major release mechanism was diffusion according to the Higuchi equation. The relative bioavailability of the ICR tablets compared to the reference formulation in the single and multiple dose regiments were 90.9 and 111.2%, respectively. They were both bioequivalent to the reference formulation. In vitro-in vivo correlation (IVIVC) studies demonstrated that the dissolution in vitro simulated the absorption in vivo well. In general, 5-ISMN ICR tablets composed of an osmotic pump tablet core and an immediate-release layer may be promising in providing immediate and constant drug delivery with minimum fluctuations during long storage time.

Topics: Adult; Algorithms; Area Under Curve; Biological Availability; Cellulose; Chemistry, Pharmaceutical; Cross-Over Studies; Delayed-Action Preparations; Drug Delivery Systems; Excipients; Half-Life; Humans; Isosorbide Dinitrate; Male; Molecular Weight; Osmosis; Polyethylene Glycols; Solubility; Tablets; Vasodilator Agents; Young Adult

A novel osmotic pump tablet with ethyl cellulose (EC) and polyvinyl pyrrolidone (PVP) as the semipermeable membrane and isosorbide-5-mononitrate (5-ISMN) as the model drug was formulated in this study. Zero order release kinetics were attained by avoiding aging during storage. Drug release increased with an increase in the percentage of PVP K30 in the semipermeable membrane. However, drug release decreased with increased coating weight. Drug release rates decreased continuously for tablets coated with EC/PEG4000 and cellulose acetate (CA)/PEG4000. This tendency was more marked with longer storage time. However, there was little change in drug release rates for tablets with a semipermeable membrane of EC/PVP K30 at 6, 12 or 24 months. The weight loss test also validated the results mentioned above. The relative bioavailability of the osmotic-pump tablets against the reference formulation in single and multiple dose regimens was 116.7 and 106.5, respectively. This means that the bioavailability of osmotic pump tablets using PVP as the plasticiser was equal to that of the reference formulation. In general, 5-ISMN osmotic pump tablets with a semipermeable membrane composed of EC/PVP K30 may be useful in providing constant drug delivery with minimum fluctuations during longer storage time.

Topics: Adult; Area Under Curve; Biological Availability; Cellulose; Chemistry, Pharmaceutical; Delayed-Action Preparations; Diuretics; Drug Delivery Systems; Drug Stability; Drug Storage; Humans; Isosorbide Dinitrate; Male; Membranes, Artificial; Osmosis; Pharmaceutic Aids; Povidone; Solutions; Young Adult

This study aimed to develop and evaluate a novel multi-unit tablet that combined a pellet with a sustained-release coating and a tablet with a pulsatile coating for the treatment of circadian rhythm diseases. The model drug, isosorbide-5-mononitrate, was sprayed on microcrystalline cellulose (MCC)-based pellets and coated with Eudragit(®) NE30D, which served as a sustained-release layer. The coated pellets were compressed with cushion agents (a mixture of MCC PH-200/ MCC KG-802/PC-10 at a ratio of 40:40:20) at a ratio of 4:6 using a single-punch tablet machine. An isolation layer of OpadryII, swellable layer of HPMC E5, and rupturable layer of Surelease(®) were applied using a conventional pan-coating process. Central-composite design-response surface methodology was used to investigate the influence of these coatings on the square of the difference between release times over a 4 h time period. Drug release studies were carried out on formulated pellets and tablets to investigate the release behaviors, and scanning electron microscopy (SEM) was used to monitor the pellets and tablets and their cross-sectional morphology. The experimental results indicated that this system had a pulsatile dissolution profile that included a lag period of 4 h and a sustained-release time of 4 h. Compared to currently marketed preparations, this tablet may provide better treatment options for circadian rhythm diseases.

Topics: Administration, Oral; Angina Pectoris; Cardiovascular Agents; Cellulose; Chemistry, Pharmaceutical; Chronobiology Disorders; Delayed-Action Preparations; Drug Carriers; Excipients; Hypromellose Derivatives; Isosorbide Dinitrate; Kinetics; Methacrylates; Methylcellulose; Microscopy, Electron, Scanning; Polymers; Solubility; Tablets; Technology, Pharmaceutical

The major aim of this study was to prepare isosorbide-5-mononitrate (5-ISMN) sustained-release pellets and evaluate their stability. The pellets were prepared by extrusion/spheronization, and then the core pellets were coated with ethylcellulose (EC 10cp) and Eudragit(®)NE30D. Here, EC was used as the subcoating agent while Eudragit(®)NE30D acted as the outer-coating agent. 5-ISMN sustained-release pellets as a novel drug delivery system contained the immediate-release portion in the outer-coating layer. Unexpectedly, 5-ISMN was found to migrate from the interior of the pellets to the surface forming needle crystals and exhibited the phenomenon of sublimation, which resulted in a tremendous increase in the release rate. Our research showed that the migration and sublimation of the active ingredient was related to the temperature and humidity. Polyvinylpyrrolidone (PVP K30) can affect the precipitation of 5-ISMN by forming a charge transfer complex between the drug and PVP, while hydroxypropyl methyl cellulose (HPMC E5) had no effect, and confirmed the correctness of this view through photographs and IR spectra. In the investigation of the stability, the results showed that there was no sublimation and migration while the pellets stored at 25°C/60%RH (ambient conditions) and 40°C/75% RH (stress conditions) during a 6-month period.

Topics: Cellulose; Chemistry, Pharmaceutical; Delayed-Action Preparations; Drug Compounding; Drug Delivery Systems; Drug Stability; Drug Storage; Excipients; Humidity; Isosorbide Dinitrate; Polymethacrylic Acids; Povidone; Solubility; Technology, Pharmaceutical; Temperature

We prepared the isosorbide-5-mononitrate pulsatile controlled-release pellets (PCRP) and studied the influencing factors in vitro. The isosorbide-5-mononitrate (5-ISMN) pellets prepared by extrusion-spheronization technology were coated with swelling material as the inner coating swelling layer, and with ethylcellulose aqueous dispersion as the outer coating controlled layer. The influences of the coating materials of the swelling layer, the coating levels of the swelling layer and controlled layer,and the pH values of the media on the release of 5-ISMN from PCRP were investigated. The drug release from the pellets was pulsatile. The ISMN-5-PCRP, with a lag time of 5 h and more than 80% released within the following 1.5 h,were prepared by using the low-substituted hydroxypropyl cellulose as the inner swelling layer with 15% (weight) in coating thickness, and the ethylcellulose aqueous dispersion as the outer controlling layer with 13% (weight) in coating thickness.

Topics: Capsules; Cellulose; Delayed-Action Preparations; Drug Carriers; Hypromellose Derivatives; Isosorbide Dinitrate; Methylcellulose

The aim of this work was to optimize time-dependent tablets using artificial neural network (ANN). The time-dependent tablet consisted of a tablet core, which contained sustained release pellets (70% isosorbide-5-mononitrate [5-ISMN]), immediate release granules (30% 5-ISMN), superdisintegrating agent (sodium carboxymethylstarch, CMS-Na), and other excipients, surrounded by a coating layer composed of a water-insoluble ethylcellulose and a water-soluble channeling agent. The chosen independent variables, i.e., X(1) coating level of tablets, X(2) coating level of pellets, and X(3) CMS-Na level, were optimized with a three-factor, three-level Box-Behnken design. Data were analyzed for modeling and optimizing the release profile using ANN. Response surface plots were used to relate the dependent and the independent variables. The optimized values for the factors X(1)-X(3) were 4.1, 14.1, and 29.8%, respectively. Optimized formulations were prepared according to the factor combinations dictated by ANN. In each case, the observed drug release data of the optimized formulations were close to the predicted release pattern. An in vitro model for predicting the effect of food on release behavior of optimized products was used in this study. It was concluded that neural network technique could be particularly suitable in the pharmaceutical technology of time-dependent dosage forms where systems were complex and nonlinear relationships often existed between the independent and the dependent variables.

Topics: Cellulose; Chemistry, Pharmaceutical; Delayed-Action Preparations; Excipients; Food-Drug Interactions; Isosorbide Dinitrate; Models, Biological; Neural Networks, Computer; Starch; Tablets; Time Factors