The distribution of water in degrading polyglycolide. Part II: Magnetic resonance imaging and drug release

This paper reports the use of magnetic resonance imaging (MRI) on polyglycolide disks to monitor the change in water ingress with degradation time. Very little response was measured before 13 days, but after this time, water began to penetrate the disks as fronts, starting from the sample surface and moving inwards towards the centre. These results provide more direct evidence in support of the four-stage degradation model for PGA outlined in previous literature, and in particular, that fairly sharp reaction-erosion fronts move in from the sample surface to the centre when the polymer is undergoing significant mass loss and water gain. A combination of MRI and drug release data suggest that fronts originate at the surface at about 7 (±2) days, and proceed at a rate of 0.033 (±0.002) mm/day. These results agree with results obtained from cumulative drug release profiles for different sample thicknesses presented in Part I. They support the hypothesis that drug releases quickly from the swollen regions behind the fronts where the polymer is open and porous, and that release finishes when the fronts meet in the centre of the sample.     

Fast and Slow Release: Synthesis of Gelatin Casted-Film Based Drug Delivery System

Present effort intends to improve the performance of gelatin based casted-films for controlled delivery of hydrophobic drugs. To achieve this goal, Piperine (a model drug) was loaded into gelatin (type A) casted-films by solvent evaporation method. Glutaraldehyde was used as a cross-linker for the gelatin films to modulate the drug release behavior and to prolong the rate of degradation of the film. In-vitro degradation study under physiological conditions and thermal analysis through differential scanning calorimetry were performed to confirm stability of the gelatin casted-film matrix. Aim was to control the drug release from films by varying the cross-linking degree and the gelatin concentration. Optical microscope analysis was performed to study the surface topography of the sample. In order to understand the drug–polymer interaction in the film, attenuated total reflectance (ATR)-Fourier transform infrared (FTIR) analysis was done. The in-vitro release study gave an overall idea of the role of cross-linkers, gelatin concentration, and effect of pH on the release profiles of Piperine. Results show that one can effectively use gelatin casted-film based drug delivery systems for a wide range of release requirements, i.e., from fast release to delayed release.     

Polyglycolide: Degradation and drug release. Part II: Drug release

This paper considers drug release from a polyglycolide (PGA) matrix and is divided into two sections. The first investigates the effects on the degradation of the polymer of incorporating a model drug, theophylline, into the polymer. Small and wide angle X-ray scattering, and mass loss and water uptake measurements indicate that the presence of this drug does not affect the time scale of the degradation process. However, the dissolved theophylline molecules affect the extent to which the polymer crystallizes during degradation. In the second section, theophylline release profiles, obtained using UV-spectrophotometry, show that the erosion of the polymer controls the release of the drug. The drug release results add further evidence to support the four stage degradation process which was described in Part I. © 2001 Kluwer Academic Publishers     

In vitro degradation and release profiles for Poly-dl-lactide film containing paracetamol

The biodegradable film containing paracetamol with suitable dimensions was prepared by polymer solution-cast method. The study mainly investigated the in vitro degradation of the films without and with 7.0% and 14% paracetamol in the phosphate-buffer saline (PBS) of pH 7.4 at 37 °C. The results showed that the degradation rate for the film with same dimensions containing more drug was faster. The in vitro drug release profiles showed that paracetamol release from film matrix was almost sustained within one month. It suggested that the biodegradable film should be potential in preventing tissue adhesion and local inflammation on operating procedure.     

Polyglycolide: degradation and drug release. Part I: Changes in morphology during degradation

The changing morphology of quenched polyglycolide (PGA) is investigated during hydrolytic degradation in phosphate buffered saline at pH 7.4. Analysis techniques include small and wide-angle X-ray scattering (SAXS and WAXS), mass measurements, DSC, pH measurement and UV-spectrophotometry. It is postulated that the degradation process can be separated into four distinct stages. In stage I, water diffuses quickly into the sample. During stage II, the polymer crystallizes by insertion crystallization, whilst the molecular weight gradually falls. This stage is characterized by a dramatic fall in the long period together with an increase in the crystallinity, minimal mass loss and minimal water uptake. At the onset of stage III, at around 10 days, a critical molecular weight is reached. Degradation products are now small enough to diffuse from the surface of the sample which begins to swell, water diffuses into the space created, and the crystals are freed from constraint. A co-operation between degradation products diffusing out of the sample and the water diffusing in causes reaction–erosion fronts to develop inside the sample. Ahead of these fronts, the trapped acidic degradation products remain to catalyze the hydrolysis. Stage III is characterized by swelling and an increase in the long period, together with mass loss and further water uptake. It is postulated that these reaction–erosion fronts move through the sample and meet in the centre at the beginning of stage IV, at which point the degradation again becomes homogeneous throughout the sample. © 2001 Kluwer Academic Publishers     

Development and validation of dissolution testings in acidic media for rabeprazole sodium delayed-release capsules

Rabeprazole sodium (RAB) dissolved in acidic media is accompanied by its degradation in the course of dissolution testing. To develop and establish the accumulative release profiles of ACIPHEX^® Sprinkle (RAB) delayed-release capsules (ACIPHEX^® Sprinkle) in acidic media using USP apparatus 2 (paddle apparatus) as a dissolution tester, the issues of determination of accumulative release amount of RAB in these acidic media and interference of hydroxypropylmethyl cellulose phthalate were solved by adding appropriate hydrochloric acid (HCl) into dissolution samples coupled with centrifugation so as to remove the interference and form a solution of degradation products of RAB, which is of a considerably stable ultraviolet (UV) absorbance at the wavelength of 298?nm within 2.0?h. Therefore, the accumulative release amount of RAB in dissolution samples at each sample time points could be determined by UV-spectrophotometry, and the accumulative release profiles of ACIPHEX^® Sprinkle in the media of pH 1.0, pH 6.0, and pH 6.8 could be established. The method was validated per as the ICH Q2 (R1) guidelines and demonstrated to be adequate for quality control of ACIPHEX^® Sprinkle and the accumulative release profiles can be used as a tool to guide the formulation development and quality control of a generic drug for ACIPHEX^® Sprinkle.     

Study of the influence of the pH media dissolution, degree of polymerization, and degree of swelling of the polymers on the mechanism of release of diltiazem from matrices based on mixtures of chitosan/alginate

The dissolution profiles of formulations based on mixtures of chitosan/alginate depend on the pH. It is possible to distinguish two processes: (a) a fast kinetic drug release up to 180 min, where the pH value changes from 1.17 to 2.21 and the drug released is controlled by the degree of polymerization and the quantity of chitosan in the formulation; (b) a low kinetic drug release between 210 and 480 min, where the pH value changes from 5.52 to 8.72 and the drug release from the matrix is controlled by the interpolymeric complex. In all formulations the order of release, according to Peppas's model in the range of fast kinetic drug release, was between 0.5 and 1.0. The mechanism of release was non-fickian diffusion, which corresponds to a coupling mechanism of diffusion and relaxation of the polymer.     

A voxel-based Monte Carlo model of drug release from bulk eroding nanoparticles

The use of polymeric nanoparticles as drug delivery devices is becoming increasingly prevalent in a variety of therapeutic applications. Despite their widespread clinical use, the factors influencing the release profiles of nanoparticle-encapsulated drugs are still not quantitatively understood. We present here a new, semi-empirical model of drug release from polymeric nanoparticles using a formulation of dexamethasone encapsulated within poly(lactic-co-glycolic acid) to set model parameters. We introduce a three-dimensional voxel-based framework for Monte Carlo simulations that enables direct investigation of the entire spherical nanoparticle during particle degradation and drug release. Due to implementation of this model at the nanoscale, we utilize assumptions that simplify the model while still allowing multi-phase drug release to be simulated with good correlation to experimental results. In the future, emerging mechanistic understandings of nanoparticle drug release may be integrated into this simulation framework to increase predictive power.     

Evaluation of two polymeric blends (EVA/PLA and EVA/PEG) as coating film materials for paclitaxel-eluting stent application

The ethylene vinyl acetate copolymer (EVA)/Poly (lactic acid) (PLA) blend and EVA/Poly (ethylene glycol) (PEG) blend were applied as the drug carrier materials for a bi-layer drug-loaded stent coating film, which consisted of a paclitaxel (PTX)-loaded layer and a drug-free EVA layer. The changes of weight and appearance of the drug-free polymeric blend films with increasing time were examined by X-ray diffraction analysis (XRD), gel permeation chromatography (GPC) tests and scanning electronic microscopy (SEM), and the results showed the degradation of PLA and the leaching of PEG from the films. The effects of PLA, PEG and drug contents on in vitro drug release were investigated, and the results demonstrated that the addition of PLA promoted the drug release while the addition of PEG almost did not. Franz cells diffusion test results indicated that the bi-layer structure successfully endowed the stent coating with the release of drug in a unidirectional fashion. The release profiles of films incorporated PTX and the mechanical performance of the film could be customized by readily adjusting the contents of the blend components. Therefore, the polymeric blends could be useful drug carrier materials for drug-loaded stent coating capable of releasing drug in a highly tunable manner.     

Mechanistic analysis of drug release from theophylline pellets coated by films containing pectin, chitosan and Eudragit RS

The objective of this study was to obtain detailed information on the mechanism of drug release from mixed-film of pectin-chitosan/Eudragit® RS. Pellets (710-840 μm in diameter) containing 60% theophylline and 40% microcrystalline cellulose were prepared by extrusion-spheronization method. Eudragit® L100-55 enteric coating capsules included film-coated pellets of theophylline in theoretical coating weight gains of 10, 15, and 20%, with pectin-chitosan complex contents of 5, 10, 15, and 20% for each level of weight gain were prepared and subjected to in vitro drug release. Drug release from this system showed a bimodal release profile characteristic with the drug release enhancement, being triggered (burst release) in the colonic medium. The reason for burst drug release may be due to the enzymatic degradation of pectin via pectinolytic enzymes in the simulated colonic medium. The mechanism of drug release from each formulation was evaluated in the terms of zero-order, first-order, Higuchi and Korsmeyer-Peppas models. It was observed that none of the enteric coating capsules showed any drug release in the simulated gastric medium (phase I). The analysis of release profiles showed that zero-order kinetics was found as the better fitting model for all formulations in the simulated small intestine (phase II) and it could be due to the pectin-chitosan swelling and subsequent formation of aqueous channels. In the colonic medium (phase III), due to degradation of pectin and its leaching from the mixed-film, there was a modification in drug release kinetics from swelling-controlled at phase II to anomalous at phase III. It also was found that both zero-order and Higuchi models contributed in colonic drug release from most of the formulations.     

Mechanistic Analysis of Drug Release from Theophylline Pellets Coated by Films Containing Pectin,Chitosan and Eudragit® RS

The objective of this study was to obtain detailed information on the mechanism of drug release from mixed-film of pectin-chitosan/Eudragit® RS. Pellets (710–840 μm in diameter) containing 60% theophylline and 40% microcrystalline cellulose were prepared by extrusion-spheronization method. Eudragit® L100-55 enteric coating capsules included film-coated pellets of theophylline in theoretical coating weight gains of 10, 15, and 20%, with pectin-chitosan complex contents of 5, 10, 15, and 20% for each level of weight gain were prepared and subjected to in vitro drug release. Drug release from this system showed a bimodal release profile characteristic with the drug release enhancement, being triggered (burst release) in the colonic medium. The reason for burst drug release may be due to the enzymatic degradation of pectin via pectinolytic enzymes in the simulated colonic medium. The mechanism of drug release from each formulation was evaluated in the terms of zero-order, first-order, Higuchi and Korsmeyer-Peppas models. It was observed that none of the enteric coating capsules showed any drug release in the simulated gastric medium (phase I). The analysis of release profiles showed that zero-order kinetics was found as the better fitting model for all formulations in the simulated small intestine (phase II) and it could be due to the pectin-chitosan swelling and subsequent formation of aqueous channels. In the colonic medium (phase III), due to degradation of pectin and its leaching from the mixed-film, there was a modification in drug release kinetics from swelling-controlled at phase II to anomalous at phase III. It also was found that both zero-order and Higuchi models contributed in colonic drug release from most of the formulations.     

Comparison of the in vitro release characteristics of mucosal freeze-dried wafers and solvent-cast films containing an insoluble drug

Drug release characteristics of freeze-dried wafers and solvent-cast films prepared from sodium carboxymethylcellulose have been investigated and compared. In vitro drug dissolution studies were performed using an exchange cell and drug release was measured by UV spectroscopy at 272?nm using distilled water. The dissolution profiles of hydrochlorothiazide from the wafers and films were compared by determining the rates of drug release, estimated from the % release versus time profiles and calculating their difference (f(1)) and similarity (f(2)) factors. The effects of drug loading, polymer content and amount of glycerol (GLY) (films) on the drug release characteristics of both formulations were investigated. Both the wafers and films showed sustained type release profiles that were best explained by the Korsmeyer-Peppas equation. Changes in the concentration of drug and GLY (films) did not significantly alter the release profiles whilst increasing polymer content significantly decreased the rate of drug release from both formulations. The rate of release was faster from the wafers than the corresponding films which could be attributed to differences in the physical microstructure. The results show the potential of employing both formulations in various mucosal drug delivery applications.     

The role of fillers and sodium metabisulfite on drug release from aged polyox tablets

Polyethylene oxides (PEOs) are extensively used to control the release rate of drugs from matrices. Unfortunately, polyox polymers are prone to oxidation under high temperature and relative humidity. The aim of this study was to investigate the effect of sodium metabisulfite as an antioxidant to overcome the drug release changes from polyox matrices (PEO 301 and 303) when stored at 40?°C. The effect of different types of fillers (lactose, mannitol and dicalcium phosphate dihydrate) on stability of diltiazem HCl release profiles was also investigated. Generally, the presence of sodium metabisulfite stabilized the release of drug from PEO matrices stored at 40?°C for 8 weeks. Whilst the absence of metabisulfite caused an increase in drug release from polyox matrices when stored at 40?°C. The results indicate that all three concentrations (0.25, 0.5 and 1% w/w) of sodium metabisulfite were able to overcome structural changes of polyox samples hence stabilizing the drug release. The results also showed that the incorporation of fillers in polyox matrices reduced the sensitivity of drug release when stored at elevated temperature. This indicates that when these excipients were used there was no need to incorporate additional antioxidant. DSC results showed that there was no difference in the melting points of fresh polyox samples and aged polyox samples containing sodium metabisulfite, whereas the melting point of aged polyox samples without sodium metabisulfite were lower than fresh polyox samples. This indicates that the presence of metabisulfite is essential to stabilize polyox samples.     

Formulation development and human in vitro-in vivo correlation for a novel, monolithic controlled-release matrix system of high load and highly water-soluble drug niacin

Novel, controlled-release formulations for high drug load, highly water soluble compound niacin based on polyethylene oxide (PEO) and hydroxypropylmethyl cellulose (HPMC) matrices were developed and investigated. The effect of sodium bicarbonate as a modulator of swelling, erosion, and drug release and its impact on changes in the kinetics of axial swelling and gel strength were evaluated by textural analysis during dissolution study. The drug release rate from PEO-based matrices was faster and correlated with lower gel strength, greater water uptake, and greater matrix erosion. Slower release rate and greater release duration correlated significantly with greater matrix swelling with negligible matrix erosion for the HPMC-based matrix system. Inclusion of sodium bicarbonate in the polymeric matrix salted out the macromolecules and increased gel strength and gel viscosity, especially in the vicinity of the swelling fronts. An in vivo study in human subjects after administration of the formulations and a commercial product exhibited similar plasma concentrations. For the formulation of interest, the mean drug fraction absorbed by the body was calculated by the Wagner-Nelson technique, and a level A “in vitro-in vivo correlation” was observed between the percent released in vitro and percent absorbed in vivo. The developed formulations appear to be robust and easy to manufacture with maximum flexibility with respect to drug dose, polymeric carriers, duration, and kinetics of drug release.     

Design of electrospayed non-spherical poly (l-lactide-co-glicolide) microdevices for sustained drug delivery

Polymer chain entanglements in organic solvents can be considered a key parameter in the formation of non-spherical beads when electrospraying is employed. The shape of micro/nanometric drug delivery systems plays a major role since it can affect circulation, extravasation, distribution and in vivo clearance of the devices. In this frame, we investigated the influence of polymer processing parameters on the design of polylactic-co-glycolic acid non-spherical microdevices loaded with triamcinolone acetonide (TrA), a sparingly water soluble corticosteroid, prepared by electrospraying technique through a one-step process. In particular, we verified that the formation of non-spherical MDs is related to the presence of entanglements among polymer chains to select the optimal solution to be sprayed. The addition of TrA did not substantially affect the particle morphology in terms of size, size distribution and circularity at all the tested drug loadings. Furthermore, the drug could be released for a prolonged period, with controlled and reproducible kinetics for over 3 weeks. The mathematical modeling of release profiles highlighted that the release is mainly driven by degradation, at a higher extent in the case of low drug loading.     

Evaluation of Xanthan Gum in the Preparation of Sustained Release Matrix Tablets

The objective of this study was to evaluate xanthan gum as a matrix former for the preparation of sustained release tablets. Preliminary experiments indicated that a fine particle sue of xanthan gum produced the slowest and most reproducible release profiles. Based on single surface experiments and tablet erosion studies, it was concluded that release of a soluble drug (chlorpheniramine maleate) and an insoluble drug (theophylline) from tablets containing low concentraions of xanthan gum was mainly via diffusion and erosion, respectively. Drug release from tablets containing xanthan gum was slightly faster in acidic media due to more rapid initial surface erosion than at higher pH. After hydration of the gum, drug release was essentially pH-independent. The amount released was directly proportional to the loading dose of drug and inversely proportional to gum concentration in tablets. Release profiles of chlorpheniramine maleate and theophylline remained unchanged after three months storage of the tablets at 40°C/80% RH and 40°C. Model tablets containing 5% xanthan gum exhibited release profiles similar to tablets containing 15% hydroxypropyl methylcellulose.     

A novel enzymatically-mediated drug delivery carrier for bone tissue engineering applications: combining biodegradable starch-based microparticles and differentiation agents

In many biomedical applications, the performance of biomaterials depends largely on their degradation behavior. For instance, in drug delivery applications, the polymeric carrier should degrade under physiological conditions slowly releasing the encapsulated drug. The aim of this work was, therefore, to develop an enzymatic-mediated degradation carrier system for the delivery of differentiation agents to be used in bone tissue engineering applications. For that, a polymeric blend of starch with polycaprolactone (SPCL) was used to produce a microparticle carrier for the controlled release of dexamethasone (DEX). In order to investigate the effect of enzymes on the degradation behavior of the developed system and release profile of the encapsulated osteogenic agent (DEX), the microparticles were incubated in phosphate buffer solution in the presence of α-amylase and/or lipase enzymes (at physiological concentrations), at 37°C for different periods of time. The degradation was followed by gravimetric measurements, scanning electron microscopy (SEM) and Fourier transformed infrared (FTIR) spectroscopy and the release of DEX was monitored by high performance liquid chromatography (HPLC). The developed microparticles were shown to be susceptible to enzymatic degradation, as observed by an increase in weight loss and porosity with degradation time when compared with control samples (incubation in buffer only). For longer degradation times, the diameter of the microparticles decreased significantly and a highly porous matrix was obtained. The in vitro release studies showed a sustained release pattern with 48% of the encapsulated drug being released for a period of 30 days. As the degradation proceeds, it is expected that the remaining encapsulated drug will be completely released as a consequence of an increasingly permeable matrix and faster diffusion of the drug. Cytocompatibility results indicated the possibility of the developed microparticles to be used as biomaterial due to their reduced cytotoxic effects.     

Formulation Development and Human In Vitro‐In Vivo Correlation for a Novel,Monolithic Controlled‐Release Matrix System of High Load and Highly Water‐Soluble Drug Niacin

Novel, controlled‐release formulations for high drug load, highly water soluble compound niacin based on polyethylene oxide (PEO) and hydroxypropylmethyl cellulose (HPMC) matrices were developed and investigated. The effect of sodium bicarbonate as a modulator of swelling, erosion, and drug release and its impact on changes in the kinetics of axial swelling and gel strength were evaluated by textural analysis during dissolution study. The drug release rate from PEO‐based matrices was faster and correlated with lower gel strength, greater water uptake, and greater matrix erosion. Slower release rate and greater release duration correlated significantly with greater matrix swelling with negligible matrix erosion for the HPMC‐based matrix system. Inclusion of sodium bicarbonate in the polymeric matrix salted out the macromolecules and increased gel strength and gel viscosity, especially in the vicinity of the swelling fronts. An in vivo study in human subjects after administration of the formulations and a commercial product exhibited similar plasma concentrations. For the formulation of interest, the mean drug fraction absorbed by the body was calculated by the Wagner‐Nelson technique, and a level A “in vitro‐in vivo correlation” was observed between the percent released in vitro and percent absorbed in vivo. The developed formulations appear to be robust and easy to manufacture with maximum flexibility with respect to drug dose, polymeric carriers, duration, and kinetics of drug release.     

Drug release profiles of ophthalmic formulations. 1. Instrumentation.

An experimental method is described for measuring time-release profiles of drugs from various ophthalmic dosage forms. This in vitro method is carried out under conditions nearly representative of those observed in vivo. Specifically, we have reproduced in vitro the small volume and the slow exchange rate of the human precorneal tear reservoir. Volumes on the order of 8-30 microL are achievable. The concentration of drug downstream from the sample reservoir is analyzed nearly continuously and the entire release profiles are appropriate for modeling. This analytical system has been used to study drug release kinetics from controlled release formulations such as gels and suspensions. The method is compared with alternative techniques.     

Eudragit NE40–Drug Mixed Coating System for Controlling Drug Release of Core Pellets

This study was aimed at developing a controlled-release coating system around core pellets with aqueous dispersion, along with some water channeling agents. Core pellets of diltiazem were prepared using the extrusion-spheronization technique and subsequently coated with aqueous dispersion of Eudragit NE40 alone, or drug–polymer mixtures using bottom-spray fluidized bed coater. The lag time in drug release profiles increased as the coating levels of Eudragit NE40 were increased, whereas no lag time was observed in core pellets coated with drug–polymer mixtures. Mixed coating at the 7% level exhibited comparatively better release profiles and provided desirable release rates during the 12-hour testing interval. Diltiazem HCl release from mixed coating was fairly independent of pH and drug loading. Curing of coated pellets was found to be an essential step for stable drug release profiles. The selection of core size range had remarkable effect on drug release rate and was considerably reduced by using greater core size.