Sustained-release Pellets Research Articles

Peroral Sustained-Release Film-Coated Pellets as a Means to Overcome Physicochemical and Biological Drug-Related Problems. I. In Vitro Development and Evaluation

In vitro preformulation testing has shown that the solubility and dissolution rate of the model drug compound ucb 11056 are highly pH dependent. Considering this, different sustained-release (SR) oral dosage forms of ucb 11056 were developed aiming to obtain the most constant and complete release of the drug during transit in the gastrointestinal (GI) tract. Classical approaches based on the use of SR formulations such as hydrophilic matrix tablets or pellets coated with one film-forming polymer (Eudragit NE30D or L30D-55) did not fulfill all expectations on the basis of their in vitro evaluation, i.e., the drug release and pattern remained highly dependent on the pH of the dissolution medium. Therefore, taking advantage of the flexibility of release adjustment obtainable from coating of pellets with different kinds of pH-sensitive film layers, a quite satisfactory pH independence of the release characteristics was obtained using formulation blends of neutral and anionic acrylic polymers. For the selected SR pellets batch 15 coated with NE30D/L30D-55 (7:3), the tridimensional topographic representation of the drug release versus time and pH showed that, notwithstanding the pH-dependent aqueous solubility of the drug, the release profiles were relatively homogeneous for any pH value ranging between 1 and 7.

Peroral Sustained-Release Film-Coated Pellets as a Means to Overcome Physicochemical and Biological Drug-Related Problems. II. Bioavailability and Tolerance Assessment in Dogs

Sustained-release (SR) dosage forms consisting of pellets coated with different pH-sensitive film layers, previously optimized in vitro with regard to pH independence of their durg release characteristics, were evaluated in vivo after single administration to Beagle dogs. In vivo performances were compared to those of a nonoptimized SR matrix tablet and a reference instant release (IR) capsule, in terms of the observed plasma pharmacokinetic profiles for the parent drug (ucb 11056) and its primary metabolite (ucb 26201), the bioavailability results, and the drug tolerance data. All SR dosage forms were seen to be effective in prolonging the relatively short biological half-life of the compound and in reducing the incidence of concentration-related side-effects, e.g., emesis, and of behavioral symptoms, e.g., restlessness, discomfort, and indisposition. The film-coated SR pellets offer a number of advantages over the monolithic SR matrix system in terms of a drug delivery pattern less dependent on pH changes in the gastrointestinal (GI) tract, a higher flexibility for adjusting and controlling the pharmacokinetic profiles, and a consequently more efficient approach for keeping all concentration-related side-effects under control.

Comparative Bioavailability of Sustained-Release Morphine Sulfate Capsules versus Pellets

Kadian™ is an oral formulation of sustained-release morphine sulfate pellets contained in a gelatin capsule, indicated for the treatment of moderate to severe chronic pain. A randomised, single-dose, open-label, 4-way crossover study in 25 healthy male and female volunteers evaluated whether in the fasted and fed state Kadian™ capsules swallowed whole were bioequivalent to Kadian™ pellets sprinkled on apple sauce. A 50mg dose of study medication was administered 7 days apart after either an overnight fast of 10 hours or after a standard high-fat meal. Serial blood samples were taken for 48 hours postdose and were analysed for morphine by high-performance liquid chromatography using electrochemical detection. Kadian™ capsules swallowed whole and Kadian™ pellets sprinkled on apple sauce were bioequivalent fasted. Furthermore, Kadian™ capsules swallowed whole were bioequivalent when given both fasted and fed, and Kadian™ capsules swallowed whole and Kadian™ pellets sprinkled on apple sauce were bioequivalent under fed conditions. Both the 90% confidence intervals and mean ratios were within the bioequivalence limits for area under the plasma morphine concentration-time curve (AUC0–48and AUC0-∞) for Kadian™ pellets sprinkled on apple sauce administered under fed and fasted conditions. However, food reduced the mean maximum plasma drug concentration (Cmax) value to 79% of the fasted value, which was just outside the lower bioequivalence limit. Because the extent of absorption of morphine from Kadian™ pellets was not significantly affected by food, this reduction in Cmax would not be clinically significant on a once-a-day administration regimen. This study confirmed and extended previous results derived in vitro that showed that the rate of release of morphine from Kadian™ pellets was not affected when the pellets were poured on to foodstuffs and liquids. In conclusion, Kadian™ capsules swallowed whole were bioequivalent to Kadian™ pellets sprinkled on apple sauce in both the fed and fasted states. Therefore, because it can be administered via an alternative dosing method (sprinkling), which is not possible with other long-acting morphine products, Kadian™ may well offer a significant advantage in the management of patients with cancer pain, particularly those with general debility or difficulty in swallowing. Kadian™ is also know as either Kapanol™ or Morcap SR™.

Optimization of propranolol hydrochloride sustained release pellets using a factorial design

A conventional pan coating method was used to prepare propranolol–HCl sustained release coated pellets. Eudragit RS was used for controlling release. A 32 full factorial design was selected and nine experimental runs were performed to improve dissolution characteristics of the sustained release formulation. The independent variables were: plasticizer concentration in the coating and volume of coating dispersion applied to the pellets in the coating pan. Optimization was performed in order to maximize the fraction of propranolol released after 12 h with respect to constraints applied to the model after 1 h and 6 h release period. The optimized formulation provided dissolution rates that were close to predicted values. A non-linear fitting of `in vitro' dissolution data for the optimized formulation was performed. The kinetics of dissolution was shown to follow the Hixon–Crowell model.

Nimodipine's protection against corticosterone-induced morphological changes in the hippocampus of young rats

Sustained high levels of corticosterone (CORT), one of the major stress-induced hormones in the rat, were suggested as generating `accelerated brain aging' and were shown to induce both specific brain changes in the hippocampus and learning impairments in young and middle-aged Fischer-344 rats. Evidence that altered calcium (Ca) homeostasis may play a major role in brain aging has accumulated over the last decade. Recently, new data established a connection between glucocorticoids and voltage-activated Ca influx in aged hippocampal neurons. In the present study, an attempt was made to block the CORT-induced `accelerated aging' by the simultaneous administration of the L-type Ca channel blocker nimodipine. CORT or placebo sustained-release (SR) pellets were implanted subcutaneously in 3 months old Fischer male rats. Each group was further sub-divided between nimodipine and placebo SR treatments. Characteristic CORT-induced morphological changes were observed in pyramidal hippocampal cells, such as at the CA1 and CA4 sub-regions (22.2%±7.7 and 28.6%±8.4 of pyknotic cells without clear nuclei, respectively). Concomitant treatment with nimodipine conferred full protection against CORT-induced morphological changes (e.g. 3.2%±0.8 and 2.1%±1.9 of pyknotic cells in CA1 and CA4, n=7 rats in each group; P<0.04). The neuroprotective efficacy of nimodipine supports the theory of Ca involvement in CORT related `accelerated brain aging'.

The Effect of Polymer Coating Systems on the Preparation, Tableting, and Dissolution Properties of Sustained-Release Drug Pellets

The preparation of sustained-release (SR) drug pellets and their tablets was evaluated. Pellets containing indomethacin, pseudoephedrine hydrochloride (P-HCl), or pseudoephedrine (P) base were prepared by spraying a mixture of drug, Eudragit S-100 resins, dibutyl sebacate, and alcohol onto nonpareil seeds via the Wurster-column process. The oven-dried drug/Eudragit S-100 (DS) pellets were coated with different levels of Eudragit RS and Eudragit S-100 acrylic resins. Tablets containing P-HCl or P-base SR pellets, microcrystalline cellulose, and Methocel K4M were compressed. The solubility of the drug entity in the polymer solution was found to be the most critical factor affecting the yield and the physical properties of the resultant DS pellets. Dissolution studies of Eudragit RS coated drug pellets demonstrated that the release profiles depended not only on the physicochemical properties of the drug, particularly aqueous solubility, but also on the coating levels. The release rate profiles of the matrix tablets can be modified by varying the types of P-HCl or P-base SR pellets in the formulation. The release of drug from the matrix tablets is primarily matrix controlled.

Application of Powder-Layering Technology and Film Coating for Manufacture of Sustained-Release Pellets Using a Rotary Fluid Bed Processor

The main objective of this study was to prepare pellets in a Roto-processor using the powder-layering process onto inert nonpareils and to evaluate the applicability of the Roto-processor setup for film coating. Nonpareils were loaded with phenylpropanolamine hydrochloride and coated with ethyl cellulose polymeric dispersion (Surelease®). The drug loading was analyzed to test the eficiency of powder layering. The effect of polymer level on the drug release from the pellets and the pore size distribution in the membrane were studied. The yields for powder layering were greater than 90%. The dissolution studies on the Blm-coated pellets showed sustained release over a 10-hr period. The time required for 50% of drug release increased and the mean pore diameter decreased with an increase in polymer coating.

Various ways of modulating the release of diltiazem hydrochloride from hot-melt extruded sustained release pellets prepared using polymeric materials

Sustained release pellets were prepared using the continuous process of hot-melt screw extrusion. Diltiazem hydrochloride was used as a highly dosed, freely soluble model drug. Pellets obtained with this technique can be filled into hard gelatin capsules. It was possible to obtain in vitro release rates low enough to achieve therapeutic plasma levels for diltiazem hydrochloride with a once or twice daily administration. Firstly, the release profiles from extrudates varying in their polymer to drug ratio were analysed using a double exponential decay equation in order to discriminate between surface release and diffusion-controlled release phases. Then, to optimize the release profile of the drug the influence of different parameters, such as polymer type, addition of pore-forming additives and hydrophilic polymers, or size of the pellets was studied. With one particular inert polymer, poly (ethylene-co-vinyl acetate), the possibility of achieving a nearly zero order release without any coating was investigated. Assuming first that this could be achieved by incorporating polymers with pH-dependent behaviour, the effect of cationic and enteric additives was also evaluated. Finally, swelling agents were included into the pellets, which were able to reduce the burst release.

Nimodipine Counteracts Corticosterone-Induced Habituation Impairments

Corticosterone or placebo sustained-release pellets (4 pellets of 200 mg each, released over 90 days) were implanted subcutaneously in young Fischer-344 rats, fed with either regular food or with food containing 860 ppm of nimodipine. Following 2 weeks of treatment, the habituation of the rats to a new environment was studied. On the first test day, placebo-implanted rats explored the new environment and exhibited a characteristic habituation. On the second test day, 48 hr later, low activity was measured in the already familiar environment. This habituation was absent in corticosterone-implanted rats fed with regular food. However, corticosterone-implanted rats fed with food containing nimodipine behaved during the second test similarly to the placebo-implanted group. The data indicated that the behavioral deficit, induced in Fischer-344 rats by the high corticosterone levels, was reversed by the nimodipine treatment. Thus, nimodipine may be useful in counteracting certain prolonged stress-related cognitive impairments.

The effect of food on the gastrointestinal transit and systemic absorption of naproxen from a novel sustained release formulation

The in vivo behaviour of a novel sustained release formulation of naproxen was investigated using gamma scintigraphy in eight healthy male volunteers under fasted and fed conditions. Disintegration of the tablet into discrete sustained release pellets occurred in the stomach shortly after administration. Feeding resulted in a lag time prior to the onset of gastric emptying but food did not affect transit through the small intestine. Post-prandial administration of the sustained release formulation did not affect the disintegration of the tablet or the bioavailability of the drug.

Dose-Related Control of Allergic Rhinitis Symptoms by a H1-Receptor Antagonist

The aim of the study was to evaluate the efficacy and duration of two doses of dimethindene, in a sustained release pellet formulation, with a standardized grass pollen provocation model (Vienna Challenge Chamber, VCC). The study of 12 grass pollen-allergic volunteers (verified by case history, skin prick test and RAST) was carried out in a placebo-controlled, double-blind, cross-over design. 12 h before a 4-hour continuous challenge with permanent 1,000 Dactylis grass pollen/m3 of air in the VCC, 4 or 8 mg of dimethindene (Fenistil pellets) or an identically appearing placebo was administered in three sessions. Nasal flow and resistance, nasal secretion and subjective symptoms were recorded at 15-min intervals during this long-term challenge under reproducible conditions. In comparison to placebo, dimethindene leads to a statistically significant reduction (p < 0.05) in nasal response and clinical symptoms for at least 16 h after treatment. The efficacy of 8 mg dimethindene was superior to that of 4 mg dimethindene; however, the differences between both active treatments were not statistically significant. Therefore 4 mg dimethindene once a day is adequate for usual pollinotic disease conditions.

Evaluation of hot-melt extrusion as a new technique for the production of polymer-based pellets for sustained release capsules containing high loadings of freely soluble drugs

AbstractHot-melt screw extrusion was presented as an alternative method for producing polymer-based sustained release pellets. Special care was paid to the case of highly dosed freely soluble drugs which often pose technological problems with the usual manufacturing processes. In a preformulation study, polymers, plasticizers and drugs were selected according to various criteria including thermal stability. During these preliminary tests, the optimum extrusion conditions were defined. Four polymers were considered for extrusion trials, namely ethylcellulose, cellulose acetate butyrate, poly(ethylene-co-vinyl acetate) and a polymethacrylate derivative (Eudragit® RSPM). Pellets were produced with diltiazem hydrochloride as model drug. The surface appearance of various formulations was examined and the porosity assessed by means of mercury porosimetry. A distinct structure was found for the EVAC-based pellets. The overall porosity was less than 10%. Lastly, in vitro release of the drug showed a biphasic prof...

Enhanced acquisition of reversal training in a spatial learning task in rats treated with chronic nimodipine

Nimodipine levels we were measured in blood and brain of rats implanted SC with sustained-release pellets of nimodipine (0, 10, 20, or 40 mg). Dose-dependent levels of nimodipine were detected in both plasma and brain. These results indicated the possible usefulness of these pellets in behavioral studies where long-term treatment is required. Therefore, the effects of chronic nimodipine, using 40-mg pellets, were examined on the performance of young, middle-aged, and aged rats in the Morris water maze. Following implantation of either nimodipine or placebo pellets, rats were trained for 6 days (three sessions/day) followed by 6 days of reversal training. During both initial and reversal training, every sixth trial was a probe trial. During initial training, there were clear age-related acquisition deficits in place training, with no effects of chronic nimodipine. Nimodipine did, however, enhance performance of rats during the first and second probe trials of reversal training. Time spent in the training quadrant by nimodipine-treated ratswas approximately 30% longer on the first reversal probe and 35% longer on the second reversal probe than time spent in this quadrant by placebo-treated animals. These results indicate that chronic nimodipine enhances the performance of normal animals in reversal training on a spatial learning task.

The MiniWiD-Coater. III. Effect of Application Temperature on the Dissolution Profile of Sustained-Release Theophylline Pellets Coated with Eudragit Rs 30 D

AbstractTheophylline pellets were coated with Eudragit RS 30 D in a miniature fluid-bed pan coater called MiniWiD developed recently. The dispersions were plasticized with varying amounts of triethyl citrate (TEC), dibutyl phthalate (DBP), and polyethylene glycol 6000 (PEG) and applied at different temperatures ranging from 25 to 45 °C. Theophylline release was tested by dissolution using the USP Apparatus 2 (paddle) in 0.1 N hydrochloric acid under sink conditions over 6 hours.At a coating level of 4 % (0.7 mg/cm2) sustained-release profiles were obtained from dispersions plasticized with TEC or DBP. By reducing the amount of plasticizer from 20 to 10%, films with higher permeabilities were obtained. This effect was compensated by tempering the pellets at 50 deg;C for 24 hours. The coating temperature had little effect on the dissolution profiles of TEC-plasticized films and no effect on films with DBP.Coatings plasticized with 20% PEG were applied at temperatures ranging from 25 to 45 °C. These films re...

Sucralfate as a Bioadhesive Gastric Intestinal Retention system: Preliminary Evaluation

AbstractA prototype formulation of a gastric intestinal retention system was successfully developed. A matrix tablet containing sucralfate, Methocel E4M and the appropriate type of drug powder, granules or pellets was prepared using the Carver Press. Three different formulations were evaluated using three different drug entities, namely; theophylline sustained release pellets, aspirin granules and antacid powder. Tablets of these three different formulations showed remarkable adhesive characteristics onto the glass vessel in acidic medium up to at least eight hours. In addition, all three different formulations exhibited sustained release in-vitro dissolution profiles. These data imply that this gastric intestinal retention system can be used to prepare sustained release formulations.

Pharmacokinetics of Nilvadipine

Nilvadipine is absorbed rapidly and completely and its absolute bioavailability is about 14-19% because of its high first-pass metabolism. Maximum plasma levels and the extent of bioavailability increase proportionally with the dose. Nilvadipine is mainly excreted via the kidney as inactive metabolites. Slow tissue redistribution is probably the reason for the terminal elimination half-life of 15-20 h. There was a good correlation between the estimated tissue concentration and the reduction in blood pressure in patients. The use of the sustained-release pellet formulation can prevent plasma level peaks and thereby lessen the typical side effects of dihydropyridine calcium antagonists. The pharmacokinetics of nilvadipine were not affected by impaired renal function, and although the bioavailability was increased in liver cirrhosis, there was no accumulation after repeated doses. There was no effect on plasma digoxin levels. The plasma concentration of nilvadipine can be affected by either activation or inhibition of the cytochrome P450 system. The use of a sustained-release once-a-day formulation to lower the peaks in plasma levels along with nilvadipine's long terminal half-life means that this well-tolerated pharmaceutical formulation can be employed in clinical trials for the treatment of hypertension and expected to work over 24 h.

Scintigraphic and pharmacokinetic assessment of a multiparticulate sustained release formulation of diltiazem

The in vivo behaviour of a sustained release multiparticulate form of diltiazem (240 mg) has been evaluated by gamma scintigraphy in eight subjects under fasting or fed conditions. The gastric emptying of the pellet formulation was significantly influenced by the presence of food. Transit through the small intestine was unaffected by food and in the majority of cases, the formulation reached the caecum about 3–4 h after leaving the stomach. Post-prandial administration of the sustained release pellet formulation did not affect the bioavailability of the drug. The type of oral formulation (i.e. solution or pellets) appeared to affect the rate, but not the extent, of absorption with the relative bioavailability (pellets to solution) being greater than 90%.

Nimodipine improves spatial working memory and elevates hippocampal acetylcholine in young rats

The calcium channel blocker nimodipine has been reported to improve cognitive performance in aged and brain-damaged animals. In the present study, the effects of nimodipine and placebo on spatial working memory and hippocampal acetylcholine were studied in young Fischer-344 rats. Nimodipine or placebo was administered via subcutaneously implanted, sustained-release pellets. Each active pellet contained 20 mg of nimodipine and released the drug over approximately 21 days. Two days after the drug or placebo pellets were implanted, training in the 8-arm radial maze started and continued for 12 days. Rats were required to learn a win-shift strategy. Nimodipine-treated animals learned the maze more rapidly than a placebo-treated group as indicated by the number of correct choices out of the first eight arms visited ( p<0.001). Treated rats also made twice as many choices per unit time during the first week of training ( p=0.005). To assess hippocampal acetylcholine release, in vivo microdialysis was performed while animals were awake and unrestrained, 19–21 days after pellet implantation. A probe with a 3 mm semipermeable tip was placed in the hippocampus (CA1 and dentate gyrus), and individual μl dialysate samples were collected at 2 μl/min and immediately analyzed by high performance liquid chromatography with electrochemical detection. Significantly higher extracellular ACh levels were found in nimodipine-treated rats (71.4±3.6 nM; n=4) compared to controls (52.5±2.5 nM; n=5) ( p=0.003) and in another group of rats of the same age that received identical drug treatment. It appears that sustained nimodipine treatment improves working memory and increases extracellular acetylcholine release in the hippocampus of young rats.

Factors affecting drug release from a pellet system coated with an aqueous colloidal dispersion

The formulation of sustained-release pellets of dextromethorphan hydrobromide is described. The system used consisted of drug-coated sugar spheres which were then overcoated with the rate-controlling membrane. The membrane was produced by spray-coating with an aqueous dispersion of ethylcellulose containing hydroxypropyi methylcellulose. It is shown that adequate post-coating conditioning is important to ensure consistency of release rates. Conditioning at 60° C for at least l h is necessary in order to ensure that the formulations produced show no ageing effects in release rates. Drug release could be made pH-independent by a choice of proper formulation.

Effect of multiple film coverage in sustained release pellets

AbstractIt is shown that in making sustained release pellets, the effect of film laid upon film has a significant effect on the performance (dissolution characteristics) of sustained release pellets, coated with insoluble films. The penetration of liquid and drug substance in and out of the coated pellet is much more rapid than predicted by diffusion coefficients of homogeneous, cast films. General diffusional equations are obeyed.