Matrix Pellets Research Articles

Development of controlled release matrix pellets by annealing with micronized water-insoluble or enteric polymers

The purpose of this study was to develop a new method for preparing controlled release (CR) matrix pellets by annealing with water-insoluble polymers, and to elucidate a relationship between the annealing temperature of the matrix pellets and a glass transition temperature ( T g) or a minimum film-forming temperature (MFT) of the polymer/plasticizer systems that constituted the matrix pellets. The pellets containing theophylline as a model drug were prepared by the extrusion-spheronization method and subsequent annealing. The pellets were characterized mainly by pellet formation, release studies, and thermal evaluations. It was apparent that the annealing temperature for the CR matrix pellets was related to the T g and MFT of the polymer/plasticizer systems. For ethylcellulose (EC) containing 22.7% triethylcitrate (TEC), the annealing temperature required for preparing CR pellets was 80 °C, which was more than 20 °C higher than the T g and MFT of this EC/TEC system. In contrast, hydroxypropylmethylcellulose acetate succinate (HPMCAS) containing 22.7% TEC could be used to prepare CR pellets without heating. The T g of this HPMCAS/TEC system was about 60 °C and the MFT was lower than 20 °C, indicating that water can act as a plasticizer for HPMCAS and that HPMCAS/TEC pellets could be annealed at room temperature. These results suggest that MFT is a better indicator than T g for estimating annealing temperature. SEM observation showed that the EC/TEC pellets annealed at 80 °C had a matrix structure with coalesced particles. On the contrary, unannealed pellets consisted of individually distinguishable particles. The release rate of drug from the matrix CR pellets was dependent on the drug concentration and polymer to plasticizer ratio.

In vivo evaluation of matrix pellets containing nanocrystalline ketoprofen

The aim of this study was to evaluate the in-vivo behaviour of matrix pellets formulated with nanocrystalline ketoprofen after oral administration to dogs. No significant differences in AUC-values were seen between pellet formulations containing nanocrystalline or microcrystalline ketoprofen and a commercial ketoprofen formulation (reference: Rofenid® 200 Long Acting). C max of the formulations containing nano- or microcrystalline ketoprofen was significantly higher compared to reference, whereas t max was significantly lower. The in-vivo burst release observed for the spray dried nanocrystalline ketoprofen matrix pellets was reduced following compression of the pellets in combination with placebo wax/starch pellets. These matrix tablets sustained the ketoprofen plasma concentrations during 5.6 and 5.4 h for formulations containing nano- and microcrystalline ketoprofen, respectively.

Multi-unit Controlled Release Systems of Nifedipine and Nifedipine:Pluronic® F-68 Solid Dispersions: Characterization of Release Mechanisms

ABSTRACTNifedipine (N) and nifedipine:Pluronic® F-68 solid dispersion (SD) pellets were developed and characterized for drug release mechanisms from a multi-unit erosion matrix system for controlled release. Nifedipine was micronized using a jet mill. Solid dispersion with Pluronic F-68 was prepared by the fusion method. Nifedipine and SD were characterized by particle size analysis, solubility, differential scanning calorimetry (DSC), and x-ray diffraction (XRD) studies. Samples were subsequently processed into matrix pellets by extrusion/spheronization using Eudragit® L 100-55 and Eudragit® S 100 as release rate-controlling polymers. Drug release mechanisms from pellets were characterized by microscopy and mercury intrusion porosimetry; DSC and XRD studies indicated no polymorphic changes in N after micronization and also confirmed the formation of SD of N with Pluronic F-68. Pellets of N showed a 24-hr drug release profile following zero-order kinetics. Pellets of SD showed a 12-hr release profile following first-order kinetics. Aqueous solubility of N after SD formation was found to be increased 10-fold. Due to increased solubility of N in SD, the drug release mechanism from the multi-unit erosion matrix changed from pure surface erosion to an erosion/diffusion mechanism, thereby altering the release rate and kinetics.

Extrusion–spheronization of pH-sensitive polymeric matrix pellets for possible colonic drug delivery

The aim of this study was to investigate extrusion–spheronization pelletization for preparing pH-sensitive matrix pellets for colon-specific drug delivery. The effects of three independent variables (amounts of Eudragit™ S, citric acid and spheronizing time) on pellet size, shape (roundness and aspect ratio), and drug release were studied with central composite design. The pellets contained ibuprofen as a model drug, citric acid as a pH-adjusting agent, Eudragit™ S as a pH-sensitive binder and microcrystalline cellulose (MCC). The pellets were prepared with Nica extrusion–spheronizing equipment and subsequently enteric-coated using an air-suspension technique. Eudragit™ S as a pH-sensitive matrix former in pellets increased the pellet size and influenced pellet roundness. In small amounts Eudragit™ S increased pellet roundness but in larger amounts pellet roundness was reduced. Citric acid promoted the pelletization process resulting in a narrower area distribution . The pH-sensitive matrix pellet failed to delay the drug release . The combination of citric acid and enteric coating, however, delayed the drug release for 15 min in a pH 7.4 phosphate buffer.

Enteric polymers as binders and coating materials in multiple-unit site-specific drug delivery systems

The aim of this study was to develop a multiple-unit, site-specific drug formulation allowing targeting of drug release in the colon. Initially, characteristics of matrix pellets containing various enteric polymers as binders were tested. An enteric coating was then added to the formulations. Ibuprofen and furosemide were used as model drugs. The former is absorbed throughout the gastrointestinal tract, the latter only from upper parts. Methacrylate copolymers, hydroxypropyl methylcellulose acetate succinates and cellulose acetate phthalate were used as enteric polymers. The properties of the products were initially tested via dissolution studies at different pHs, then via bioavailability studies in healthy volunteers. The main conclusion was that drug release can be targeted on the distal part of the small intestine and the colon by preparing film-coated matrix pellets in which enteric polymers dissolving at pH≈7 have been used both as binders in the pellets and as coating material. This conclusion is based on the finding that absorption of ibuprofen from the formulations developed was adequate, with a lag-time of about 2 h and t max values at 4–5 h, where as absorption of furosemide from the analogous products was negligible. It was also found that uncoated pellets as such could represent a slow-release formulation for furosemide, a problem drug as far as modified-release products are concerned.

Bioavailability of ibuprofen from matrix pellets based on the combination of waxes and starch derivatives

The bioavailability of ibuprofen from pellets based on microcrystalline wax and starch derivatives was tested. During the in vivo evaluation an oral dose of 300 mg ibuprofen was administered to healthy human volunteers. F-1 and F-2 pellets were filled into hard gelatin capsules and were formulated with 60% ibuprofen, 15% waxy maltodextrin and 25% wax (a mixture of Lunacera M® and Lunacera P® (ratio 7/3) in the case of F-1 pellets and pure Lunacera P® in case of the F-2 pellets). In vitro, t 50% was 20 and 4 h for F-1 and F-2 pellets, respectively. Both formulations behaved in vivo as sustained release formulations with a HVD t 50% C max value of 6.4 and 5.6 h for F-1 and F-2, respectively. Bioavailability depended on the composition of the formulation as the C max-values were 5.3 and 8.5 μg/ml and the AUC 0→24h-values 49.0 and 75.6 μg×h/ml for the F-1 and F-2 pellets, respectively. The bioavailability of a chewable tablet, made of F-3 pellets (30% ibuprofen, 40% drum dried corn starch and 30% Lunacera P®) and showing an immediate in vitro drug release, was similar to the bioavailability of an ibuprofen suspension. The C max and AUC 0→24h of F-3 pellets were 31.9 μg/ml and 121.1 μg×h/ml, respectively. These data demonstrate that pellets based on the combination of microcrystalline wax and starch derivatives can be used to formulate sustained as well as immediate release formulations.

SAX, software for the analysis of x-ray fluorescence spectra

A program for chemical analysis by energy-dispersive x-ray spectrometry is described. Fluorescent multiplets are fitted to a high degree of accuracy by a method using an empirical energy-dependent peak-shape function derived from the spectrometer response to well resolved standard sample spectra. Elemental identification is accomplished via an interactive peak search and a complete K and L x-ray line library. Matrix correction routines for element quantification are provided for infinitely thick samples with fundamental parameters, including Compton correction, for thin samples and total reflection (TXRF) geometry and for semi-transparent light matrix pellets (emission-transmission method).

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.

Optimization of the Processing of Matrix Pellets Based on the Combination of Waxes and Starch Using Experimental Design

An experimental design was used in order to optimize the one-step production process of matrix pellets based on the combination of waxes and starch. The parameters tested were the impeller speed (x1) and the mixing time (x2). Ibuprofen and theophylline were used as model drugs at a concentration of 60 and 70% (w/w), respectively. The 0.8–1.25 mm yield fraction of the matrix pellets was evaluated as the response factor Y. A quadratic equation was fitted to the experimental data and used to predict the response factor Y of the theophylline and the ibuprofen. The contour plots of both formulations revealed a flat and therefore rugged region from the upper left to the lower right of the domain investigated. The energy input into the system during the production process controlled the pellet growth, the impeller speed having a greater impact on the energy input compared to the mixing time.

Influence of processing on the characteristics of matrix pellets based on microcrystalline waxes and starch derivatives

Matrix pellets based on microcrystalline waxes and starch derivatives were manufactured in the different types of high shear granulators with a volume ranging from 2–70 1. Ibuprofen and theophylline were used as model drugs with a loading of 60 and 70%, (w/w), respectively. The production process and the formulation of the matrix pellets had to be adapted in function of the high shear granulator used. Processing parameters influenced pellet quality. An increasing mixing time and an increasing mixing speed induced a larger pellet size and a lower porosity. For the ibuprofen pellets the lower porosity correlated well with a decrease in release rate. During production the product temperature had to be controlled within a narrow range. The release kinetics of the wax-starch system was described using the equation M t/ M ∞ = kt n. The drug release mechanism from the ibuprofen pellets is a Fickian diffusion process, while the theophylline pellets were characterized by a non-Fickian release mechanism.

Influence of process parameters on the characteristics of matrix pellets based on the combination of microcrystalline waxes and starches

Influence of process parameters on the characteristics of matrix pellets based on the combination of microcrystalline waxes and starches

Matrix pellets based on the combination of waxes, starches and maltodextrins

Matrix pellets were produced combining microcrystalline waxes, pregelatinized starches and hydrolysed starches. Ibuprofen, sodium salicylate, benzoic acid, sodium benzoate and chloroquine phosphate were used as model drugs. Using a wax with a melting range between 68 and 72°C and increasing the wax concentration decreased the drug release rate. Pellets containing drum-dried corn starch failed to form matrix pellets. The slowest drug release was obtained for formulations containing waxy maltodextrin, releasing 95% of the incorporated ibuprofen after 48 h in vitro. Increasing the ibuprofen concentration decreased the drug release rate. Drug release was controlled by pore and matrix diffusion. The release of sodium salicylate and sodium benzoate from the wax-starch matrix pellets was characterised by an initial burst release followed by a block of the drug release.

Some factors influencing the formation and in vitro drug release from matrix pellets prepared by extrusion/spheronization

A statistically designed experiment has been undertaken to evaluate the influence of formulation factors on the formation and drug release from pellets formed by the process of extrusion/spheronization. The influence of drug solubility, drug content, the quantity and type of release modifying agent and the quantity and type of filler on the process and properties was divided into two sections and the relationship indicated by canonical analysis, a multivariate analysis procedure. The first section considered the influence of the formulation variables on median pellet size, the steady-state extrusion force and the ratio of Avicel to water, while the second section considered the influence of the formulation variables on the in vitro drug release, as measured by the AUC and MDT of the percentage drug release time profile. The molecular weight of the polyethylene glycols was shown to be the main factor influencing the median pellet size and steady-state extrusion force. The water content required for good formulations was reduced significantly by the inclusion of polyethylene glycols, whereas the presence of glyceryl monostearate at differing levels did not influence the water level required. The analysis of the influence on drug release was not, however, so clear. Important factors appeared to be the drug solubility and choice of filler. The lower the drug solubility the larger the value of the AUC and MDT. Formulations containing barium sulphate have larger AUC and MDT values than those containing lactose. The presence of glyceryl monostearate or polyethylene glycol is not a factor significantly influencing drug release.

Prolonged Release Matrix Pellets Prepared by Melt Pelletization II. Hydrophobic Substances as Meltable Binders

12 meltable substances were studied with respect to their ability to form prolonged release pellets in a melt pelletization process using a laboratory scale high shear mixer. It was found that few substances were able to pelletize a formulation with 12.5% m/m paracetamol and 87.5% m/m calcium hydrogen phosphate. Favourable technical features of glyceryl monostearate were combined with release prolonging features of more hydrophobic substances. Pellets prepared with combinations of glyceryl monostearate and microcrystalline wax demonstrated the slowest release. The release of drug could be varied within wide limits by varying the composition of the binder phase.

Factors influencing the mechanism of release from sustained release matrix pellets, produced by extrusion/spheronisation

Spheres have been prepared from a wet mass by extrusion and spheronisation. Chitosan was included as a solution in the powder mix. Four formulations were considered, containing two different concentrations of chitosan, each prepared at two different sizes of sphere; either approx. 1 or 2 mm. The release of a model drug (diclofenac sodium) from the spheres was found to be considerably slower than formulations without added chitosan (i.e. ca. 100% in 6 h, rather than 30 min). Thus it is possible to retard drug release from a sphere, without the need for polymer coating, by use of a hydrophilic gel. The drug release profiles followed first order kinetics (for all four systems), and produced a straight line when plotted as a function of the square root of time. A straight line was also obtained when a double logarithmic plot of release as a function of time was prepared, the gradient of which was in the order of 0.5, this would indicate Fickian diffusion, if from a thin slab, but as the release was from a sphere, the process was described as fitting a non-Fickian diffusion model. Dissolution testing at different stirring speeds did not alter the rate of drug release, demonstrating that the diffusion process was controlled within, rather than in the layer of fluid around, the sphere. Thermodynamic activation parameters were calculated and the four formulations were compared by compensation analysis. It was apparent that there was no common mechanism for drug release, but that the concentration of the Chitosan related to the enthalpy change, and the Gibbs free energy change correlated with the dissolution rate.

Prolonged release Matrix Pellets Prepared by Melt Pelletization I. Process Variables

AbstractA melt pelletization process was investigated in an 8 litre laboratory scale high shear mixer using a formulation with paracetamol, glyceryl monostearate 40–50, and microcrystalline wax. The effects of jacket temperature, product temperature during massing, product load, massing time and impeller speed were investigated by means of factorially designed experiments. The maximum yield of pellets in the range of 500–1400μm was found to approx. 90%. For process conditions preventing deposition of moist mass, the process was found to be reproducible. Impeller speed and massing time were found to be important process variables. Remarkably low in vitro drug release rates were observed in USP-dissolution tests.

Preoperative versus postoperative irradiation in the prophylaxis of heterotopic bone formation in rats

Irradiation treatment, commenced within 1–5 days post-surgery, reliably prophylaxes heterotopic bone formation but is painful and impairs desirable postop immobilization. To compare pre- versus post-op radiation, we bilaterally implanted bone matrix pellets into the thighs of 111 30-day-old Long Evans rats. Rats were randomized to time of radiation initiation (2 days pre-op, 1 hr pre-op, or 2 days post-op) and dose (300, 800, 1800, 2400, or 3000 cGy in 1 fraction). Pellets were removed on post-op day 16 or 48 and evaluated histologically and radiologically. Histologic analysis showed dose-related suppression in bone formation, that is, 40%, 27%, 6.8%, 2.5%, 6.4%, and 0.0% bone formed among sites receiving 0, 300, 800, 1800, 2400, and 3000 cGy, respectively. The difference in bone formation between control and irradiated implant sites was significant at every dose level in all treatment groups (p ≤ .03). There was no statistically significant difference in overall bone formation between post-op (7.1%) and 1 hr pre-op (5.3%) groups, whereas 2 day pre-op rats formed significantly more bone (12.6%). Stratified by dose, however, there were no significant differences between treatment groups except at 800 cGy. At this dose, 2 day pre-op rats formed more bone (10.6%) than 1 hr pre-op (6.6%) or post-op (3.3%) groups. Results suggest that a) radiation given shortly prior to a stimulus inducing proliferation among multipotential cells may inhibit subsequent proliferation and/or differentiation, and b) clinical formation of heterotopic bone may be preventable via modest doses of irradiation delivered shortly prior to surgery.

Preoperative vs postoperative irradiation in the prevention of heterotopic bone formation

Prophylaxis of heterotopic bone formation is reliably accomplished via postoperative irradiation. Because of apparent need to initiate irradiation within l-5 days post surgery, this treatment is however quite painful. An analog study was therefore designed to assess comparative efficacy of pre versus post op irradiation.. Decalcified bone matrix pellets (10 mg each) were bilaterally implanted superficial to the roughened anterior thigh fascia of 95, 30 day old, Long Evans rats. irradiation (2 days pre-implant, Rats were randomized to, a) time of 1 hour pre-implant or 2 days post-implant), b) dose (800, 1800, 2400 or 3000 cGy in 1 fraction), and, plus 2 cm margin. c) target volume (left or right implant site Implants were removed at postop day + 16 and subject to morphometric and microradiographic analysis of percent bone development within each extracted pellet site. Results indicate that postop rats formed no bone at any of the dose levels. One hour and 2 day preop rats formed 7.6% and 10.0% bone respectively at 800 cGy. With the exception of one 2400 cGy rat in each preop group, formed no bone at 1800, all other 1 hour and 2 day preop rats 2400, and 3000 cGy dose levels. Analysis of variance showed no significant differences among any of the 3 treatment groups at any dose level. To further control for unknown host variables affecting the degree of bone formation, bone formation within each rat's irradiated implant was subtracted from degree of bone formation of the unirrddiated pellet site to thus form percent bone formation scores. Difference scores among postop, 1 hour preop and 2 day preop groups respectively were similar at 800 cGy (30.2, 20.8, 37.5%), 1800 cGy (35.7, 46.6, 37.3%), and 3000 cGy (42.1, 38.7, 35.7%). At no dose level did the discrepancy between difference scores reach statistical significance. Results of microradiographic analysis of percent bone formation, and densiometric analysis of comparative degree of calcium incorporation were similar to morphometric findings. Results suggest no differences at dose levels employed in terms of suppression of bone formation among rats irradiated postoperatively versus 1 hour or 2 days preoperatively. This suggests efficacy of irradiation delivered shortly prior to stimulus for proliferation to subsequently inhibit such proliferation. We are currently comparing utility of pre vs post op irradiation at lower doses (to 300 cGy) and at longer time intervals to sacrifice (48 days). Current results hint that development of heterotopic bone following hip surgery among our patients may be preventable by irradiating relevant hips shortly prjo_r_ to surgery at currently employed post operative dose levels and thus spare such patients the discomfort associated with postoperative irradiation.

Antagonism by an LHRH agonist of the steroidogenic effects of exogenous human chorionic genadotrophin in the rhesus monkey

Fourteen regularly cycling female rhesus monkeys were observed daily for menstruation and bled from the saphenous vein at regular intervals throughout the study. Plasma samples were assayed by RIA for progesterone levels. The animals were divided into 3 subgroups. The first (n=5) received daily subcutaneous injections of 1000 IU hCG from the 18th to 36th day following onset of menstruation. The second (n=7) received the same hCG treatment and was also implanted subcutaneously from the 18th to 40th days with 1.2 mg [Des-gly 10, DTrp 6, ProNHEt 9] LHRH contained in cholesterol matrix pellets. The third (n=2) was untreated. Intermenstrual interval was significantly extended by hCG treatment. The extension was partially overcome by the LHRH agonist. The hCG-induced elevation in plasma progesterone to peak values over 17ng/ml was blocked by the LHRH agonist to give mean values not significantly different from control luteal phase levels. Plasma estradiol levels were unaffected by hCG or LHRH agonist.

Effects of coating on the release profile of drug combination from hydrophilic matrix pellets

In this work zinc sulfate, ferrous sulfate and ascorbic acid was formulated on the same pellet by combination pelletization technique and their and in vitro dissolution studies were performed by using United States Pharmacopoeia (USP) apparatus type II. In addition, effect of different types of polymers, formulation variables and variations in coating composition on the release of drug were studied. The desired release profile for ferrous sulfate was 35% for 1st hour, 45-75% for 2nd hour and 60-85% for third hour and not less than 85% for 4th hour. The release rate controlling polymer used was various concentrations of Methoccel K15M CR with different concentrations of Microcrystalline cellulose (Avicel PH 101). The maximum release percentage of Ferrous Sulphate was obtained from 2.5 % of Methocel K15M CR and 30 % Avicel PH 101 containing pellets (F-4) and it was 92.32%. And the minimum release percentage of Ferrous Sulphate was obtained from 10 % of Methocel K15M CR and 35.7% Avicel PH 101 containing pellets (F-1) and it was 86.36%. The release profile from other formulations containing 35.4% Methocel K 15M CR & 7.5% Avicel (F-2) and 32% Methocel K 15M CR & 4% Avicel (F-3) were also within desired range. The effect of Eudragit coating (enteric) and the presence of PEG and HPMC in the film coating composition on the drug release were also investigated. Hydrophobic matrix pellets prepared using lower concentrations of Methocel K15M CR were found to be best suited for modulating the delivery of the ferrous sulphate from the combination. Key words: Non Pariel Seeds (NPS); Pan Coater; Ascorbic acid; Methocel K15M CR; Pelletization; PEG; Avicel PH 101; Xanthan gum.DOI: 10.3329/sjps.v2i2.5824Stamford Journal of Pharmaceutical Sciences Vol.2(2) 2009: 53-58