Controlled-release Pellets Research Articles

Statistical Optimization of Tamsulosin Hydrochloride Controlled Release Pellets Coated with the Blend of HPMCP and HPMC

The objective of the present study was to evaluate three coating parameters for the application of a blend of HPMCP and HPMC in ethylcellulose aqueous dispersions (Surelease) in order to obtain controlled release of tamsulosin hydrochloride. The selected independent variables, HPMCP content (X1), HPMC content (X2) and coating level (X(3)), were optimized with a three-factor, three-level Box-Behnken design. The selected dependent variables were the cumulative percentage values of tamsulosin hydrochloride that had dissolved after 2, 3 and 5 h. Various dissolution profiles of the drug from controlled release pellets were obtained. Optimization was performed for X1, X2 and X3 using the following target ranges; 15% < or = Y1 < or= 30%; 50% < or = Y2 < or = 65%; 80% < or = Y3 < or = 95%. Results of the optimization procedure indicated that the optimized levels of HPMCP content (X1), HPMC content (X2) and coating level (X3) were 30%, 15% and 25%, respectively. Controlled release pellets coated with the optimized formulation provided a release profile that was close to predicted values. In addition, the dissolution profiles of the controlled release pellets coated with the optimized formulation were similar to those of the commercial product Harunal capsule (f1 = 4.6, f2 = 78.7).

Optimization of tamsulosin hydrochloride controlled release pellets coated with Surelease and neutralized HPMCP

This study was to optimize the coating level in the development of controlled release pellets coated with Surelease and neutralized hydroxypropyl methylcellulose phthalate (HPMCP) by a computer optimization technique based on a response surface methodology utilizing polynomial equation. A full factorial 3(2) design was used for the optimization procedure with coating level (X(1)) and HPMCP content (X(2)) as the independent variables. The drug release percent at 2, 3 and 5 h were the target responses, which were restricted to 12-39% (Y(1)), 44-70% (Y(2)) and 70-100% (Y(3)), respectively. The quadratic model was well fitted to the data, and the resulting equation was used to predict the responses in the optimal region. It was shown that the optimized coating formulation was achieved at the ratio of 3:1 (Surelease: neutralized HPMCP) with 20% coating level. The optimized formulation showed release profiles and responses, which were close to predicted responses. Therefore, a full factorial 3(2) design and optimization technique can be successfully used in the development of optimized coating formulations based on Surelease and neutralized HPMCP to achieve a controlled release drug delivery system containing tamsulosin hydrochloride.

Gastrointestinal Transit Monitoring and Absorption of Controlled-Release Pellets of Diltiazem

Gastrointestinal Transit Monitoring and Absorption of Controlled-Release Pellets of Diltiazem

The influence of Surelease and sodium alginate on the in-vitro release of tamsulosin hydrochloride in pellet dosage form

The objective of this study was to prepare controlled-release pellets containing 0.2 mg tamsulosin hydrochloride using a pelletizer-equipped piston extruder and double-arm counter-rotating rollers with Surelease and sodium alginate. The release of tamsulosin HCl from pellets coated with the commercial aqueous ethylcellulose dispersion (Surelease) was investigated at different coating loads. In addition, the effect of sodium alginate on drug release was investigated by varying the ratio of sodium alginate to microcrystalline cellulose (MCC). Dissolution studies were first performed in 500 mL simulated gastric fluid (pH 1.2) containing 0.003% (w/w) polysorbate 80 and then in simulated intestinal fluids (pH 7.2). The morphology of pellet surfaces and cross sections were examined by scanning electron microscopy (SEM). Apparently, the spherical pellets were prepared using a pelletizer-equipped piston extruder and double-arm counter-rotating rollers. The release profiles of tamsulosin HCl from Surelease-coated pellets were significantly affected by changing the content of Surelease, the pH of the dissolution medium and the ratio of sodium alginate to MCC. The drug release rates not only decreased with increase in the coating load, but also increased when the pH of the dissolution medium was increased from 1.2 to 7.2 regardless of the sodium alginate-to-MCC ratio. Moreover, the drug release rate at pH 7.2 was gradually increased by increasing the ratio of sodium alginate to MCC. SEM showed smooth surfaces of Surelease-coated pellets. These results suggest that Surelease and sodium alginate would be useful excipients in the preparation of controlled-release pellets with the desired release profiles.

Compression of Controlled-Release Pellets Produced by a Hot-Melt Extrusion and Spheronization Process

Compression of Controlled-Release Pellets Produced by a Hot-Melt Extrusion and Spheronization Process

Compression of Controlled-Release Pellets Produced by a Hot-Melt Extrusion and Spheronization Process

The purpose of this study was to investigate the physicomechanical and dissolution properties of tablets containing controlled-release pellets prepared by a hot-melt extrusion and spheronization process. A powder blend of anhydrous theophylline, Eudragit® Preparation 4135 F, and functional excipients was melt-extruded, pelletized, and then spheronized. The pellets were compressed into tablets using forces of 5, 10, 15, and 20 kN. Tablet diluents included microcrystalline cellulose, a mixture of spray-dried lactose and microcrystalline cellulose, modified food starch, and soy polysaccharides. The effective porosity of the compressed pellets was measured using mercury porosimetry and helium pycnometry, while the surface area was determined using Brunauer, Emmett, and Teller (BET) analysis. The disintegration time, hardness, and friability of compacts were determined. Drug release studies were performed according to USP 27 Apparatus 3 guidelines in 250 mL of medium (pH 1.0, 3.0, 5.0, 6.8, and 7.4) 37°C and 20 dpm. Samples were analyzed by high pressure-liquid chromatography (HPLC). Effective porosity and surface area determinations of the melt-extruded pellets were not influenced by compression. The percent of theophylline released from rapidly disintegrating tablets was not affected by compression force or excipient selection, but tablets with prolonged disintegration times exhibited delayed drug release in acidic media. However, dissolution profiles of uncompressed pellets and all compacts were identical after transition from 0.1 N HCl to media increasing in pH from 3.0 to 7.4. Furthermore, pellet to filler excipient ratio and filler excipient selection did not influence the rate of drug release from compacts.

Gastrointestinal Transit Monitoring and Absorption of Controlled-Release Pellets of Diltiazem

The gastrointestinal (GI) transit and absorption of a multiparticulate controlled-release diltiazem formulation were investigated with reference to an innovator preparation. Transit of controlled-release pellets in GI tract was monitored using two marker drugs, namely paracetamol and sulfasalazine. Both formulations had little intersubject variation in gastric emptying and small intestine transit time. In both formulations, about 51% to 64% of the drug was absorbed while pellets were in the small intestine and the remaining amount while in the colon. The results found in this study were comparable to the other workers who used gamma scintigraphy or indirect method. Therefore, the method used in this study is a reliable alternative for studying GI transit of pellets.

Prostaglandin E 2 enhances alveolar bone formation in the rat mandible

Prostaglandin E 2 (PGE 2) induces bone formation in stress-bearing bones. The mandible, a stress-bearing bone, is loaded daily during mastication. The aim of this study was to determine if PGE 2 delivered locally to the mandible over 20 days enhances alveolar bone deposition. In 18 Lewis rats, controlled-release pellets containing PGE 2 were implanted on the buccal aspect on the left-hand side of the mandible, mesial to the root of the first molar. Controlled-release pellets locally delivered 0.1, 0.05, or 0.025 mg/day of PGE 2. The right side of the mandible was used as a matched control for each animal. Six sham-treated animals were implanted with a placebo pellet. On days 7 and 19, animals were injected with the bone markers tetracycline and calcein, respectively. On day 21, animals were sacrificed and undecalcified tissues obtained for morphometrical analysis. Morphometrical measurements were analyzed by paired t test to determine differences between the matched samples and one-way ANOVA to compare the different treatment groups. A significant increase in alveolar bone area was observed in mandibles treated with 0.1 and 0.05 mg/day when compared with matched controls and the placebo group. This was accompanied by a significant increase in alveolar bone height and width. The proportions of double-labeled surface (dLS), the mineral apposition rate (MAR), and bone formation rate (BFR) were significantly increased in mandibles treated with the two higher doses of PGE 2. The proportion of resorptive surface (RS) was significantly reduced in these two groups. It is concluded that PGE 2 induces alveolar bone formation in the mandible when locally delivered at a dose of 0.1 or 0.05 mg/day for 20 days.

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.

Prevention of auditory dysfunction in hypothyroid Tshr mutant mice by thyroxin treatment during development.

Based on previous work, it is clear that genetically hypothyroid Tshr(hyt) mutant mice are congenitally deaf [O'Malley et al. (1995) Hear. Res. 88: 181-189, Sprinkle et al. 2001b, J. Assoc. Res. Otolaryngol. DOI: 10.1007/s101620010077]. However, the extent to which auditory development is dependent on the availability of thyroxin (T4) during specific developmental stages is unknown. The aim of this study was to determine the relative importance of prenatal and postnatal thyroxin on the ontogeny of hearing in the hyt mouse. Experimental hypothyroid subjects were offspring of hyt/hyt breeders implanted with T4 or placebo controlled-release pellets 14 days prior to mating. Pups received T4 or saline placebo injections from birth through postnatal day 14 (P14) or the time of testing on P28. In the absence of exogenous T4 replacement, very high stimulus levels (>80 dB SPL) were required to elicit responses. Remarkably, T4 treatment confined to the postnatal period failed to significantly improve auditory function relative to untreated animals, while response thresholds, latencies, and amplitudes of mice born to dams that received T4 during pregnancy were significantly improved relative to both of the untreated groups. Response thresholds were improved somewhat when maternal T4 replacement was followed by treatment during the first 14 days of life, and animals treated throughout prenatal and postnatal life were comparable to those of age-matched euthyroid individuals. Findings from this study show that treatment of hyt/hyt mice with exogenous T4 significantly attenuates hypothyroid-induced otopathology in a develop-mental-stage-dependent manner. In addition, we demonstrate that postnatal development is critically dependent on prenatal exposure to thyroxin and that the critical window of T4 dependence extends throughout development.

An oral controlled release matrix pellet formulation containing nanocrystalline ketoprofen

A controlled release pellet formulation using a NanoCrystal ® colloidal dispersion of ketoprofen was developed. In order to be able to process the aqueous NanoCrystal ® colloidal dispersion into a hydrophobic solid dosage form a spray drying procedure was used. The in vitro dissolution profiles of wax based pellets loaded with nanocrystalline ketoprofen are compared with the profiles of wax based pellets loaded with microcrystalline ketoprofen and of a commercial sustained release ketoprofen formulation. Pellets were produced using a melt pelletisation technique. All pellet formulations were composed of a mixture of microcrystalline wax and starch derivatives. The starch derivatives used were waxy maltodextrin and drum dried corn starch. Varying the concentration of drum dried corn starch increased the release rate of ketoprofen but the ketoprofen recovery remained problematic. To increase the dissolution yield surfactants were utilised. The surfactants were either added during the production process of the NanoCrystal ® colloidal dispersion (sodium laurylsulphate) or during the pellet manufacturing process (Cremophor ® RH 40). Both methods resulted in a sustained but complete release of nanocrystalline ketoprofen from the matrix pellet formulations.

Trimetazidine: stability indicating RPLC assay method.

An accurate, specific and reproducible reversed phase liquid chromatographic method for the determination of trimetazidine hydrochloride in presence of its degradation products is reported. The mobile phase consisted of water-acetonitrile-triethylamine (90:10:0.1, v/v/v) adjusted with o-phosphoric acid to a pH of 3.3. Chromatography was performed using C-18 column at a flow rate of 1.0 ml/min and the drug along with its degraded products was detected at 270 nm. The calibration curve of trimetazidine hydrochloride in methanol was linear in the range 500-3000 ng. The mean value of correlation coefficient, slope and intercept were 0.99859 &# 0.001, 17.7986 &# 0.0709 and 482.56 &# 147.03, respectively. The limits of detection and quantitation were 5 and 20 ng, respectively. The recovery of trimetazidine hydrochloride was about 99-100%. This method was utilized to analyze trimetazidine hydrochloride from conventional tablets and controlled release pellets in the presence of commonly used excipients.

Stability indicating HPTLC determination of Trimetazidine as bulk drug and in pharmaceutical formulations.

A simple, selective, precise and stability-indicating high-performance thin-layer chromatographic method of analysis of trimetazidine hydrochloride both as a bulk drug and in formulations is reported. The mobile phase composition was n-butanol-water-methanol-ammonia (20%) (14:0.2:0.2:2, v/v/v/v). Densitometric analysis of trimetazidine hydrochloride was carried out in the absorbance mode at 254 nm. the calibration curve of trimetazidine hydrochloride in methanol was linear in the range 400 -- 2400 ng. The mean value of correlation coefficient, slope and intercept were 0.99815 and #61617;0.001, 0.4849 and #61617;0.001 and 31.633 and #61617;5.996 respectively. The limits of detection and quantitation were 50 and 80 ng respectively. The recovery of trimetazidine hydrochloride was about 98 -- 100%. This method was utilized to analyze trimetazidine hydrochloride from conventional tablets and controlled release pellets in the presence if commonly used excipients.

Formulation Optimization of Controlled-Release Pellets of Metoclopramide Hydrochloride Using Dissolution Fit Factor Approach

The purpose of this study was to optimize the formulation variables for the preparation of ethyl cellulose-coated nonpareils loaded with metoclopramide hydrochloride (MCL). The approach to evaluate the effectiveness of formulation parameters was monitored by release rate testing using dissolution fit factors as a tool. The content of ethyl cellulose used in the formulation was based on the drug-loaded weight. The interrelationship of each developed formulation and the reference formulation Gastro-Timelets® and their respective dissolution curves were evaluated using Moore's equation: f2 = 50 × log {[1 + 1/n ∑nt = 1 Wt(Rt − Tt)2]−05 × 100}. The relationship between the ethyl cellulose content in the formulation and the dissolution fit factor f2 can be described as the following regression equation: Y = −0.054X2 + 3.347X − 1.915 (r2 = 0.99). The optimum ethyl cellulose content obtained from the equation was 30.8%. The type and content of plasticizer used in the formulation to achieve the greatest f2 were determined to be Myvacet 9–40 at the concentration of 25%. Results indicated that using the release rate testing approach with the dissolution fit factor as a tool could provide valuable information for formulation optimization.

Ouabain- and central sodium-induced hypertension depend on the ventral anteroventral third ventricle region.

To examine the role of the ventral anteroventral third ventricle (vAV3V) in the hypertension induced by chronic subcutaneous ouabain and intracerebroventricular hypertonic saline, neurons in this area were destroyed by microinjection of an excitotoxin, ibotenic acid. Sham-operated or lesioned Wistar rats were administered ouabain (50 microgram/day) or placebo for 3 wk from subcutaneously implanted controlled release pellets or artificial cerebrospinal fluid (CSF) or CSF containing 0.8 mol/l NaCl (5 microliter/h) infused intracerebroventricularly for 2 wk. At the end of the experiment, mean arterial pressure (MAP) and heart rate at rest and in response to ganglionic blockade by intravenous hexamethonium (30 mg/kg) were assessed. In rats infused with hypertonic saline, responses to air jet stress were also assessed. Baseline MAP in sham-operated rats receiving intracerebroventricular hypertonic saline or subcutaneous ouabain was significantly higher than in control rats (115 +/- 1 vs. 97 +/- 3 and 121 +/- 3 vs. 103 +/- 3 mmHg, respectively). vAV3V lesions abolished the increase in MAP elicited by chronic infusion of hypertonic saline or administration of ouabain. Sham-operated rats treated with hypertonic saline or ouabain exhibited significantly enhanced decreases in MAP to hexamethonium, but lesioned rats did not. Rats infused with hypertonic saline demonstrated enhanced responses to air jet stress that were similar in sham-operated and lesioned rats. These results demonstrate that neurons in the vAV3V are essential for the hypertension induced by intracerebroventricular hypertonic saline and subcutaneous ouabain, possibly by increasing sympathetic tone. Cardiovascular responses to air jet stress appear not to be mediated by the vAV3V.

Stochastic modeling of controlled-drug release

A drug release process by the oral route is random in nature and thus is subject to constant fluctuations. Moreover, individuals have varied tolerances to such fluctuations. The objective of this work is to characterize these fluctuations by a stochastic formalism. The system under consideration, i.e., the gastrointestinal tract consists of four consecutive compartments, i.e., stomach, duodenum, jejunum, and ileum. The master equation of the system as well as the governing equations for the means, variances, and covariances of the random variables, each representing the number of microspheres in an individual compartment, have been derived through the probabilistic population balance. These equations have been numerically solved to predict the total release fraction of drug and its internal fluctuations, and the dynamic statistics (means, variances, and covariances) of the amount of drug in each compartment at any time after administration. The dissolution-intensity functions in the model have been recovered from the available in vitro dissolution data from controlled-release pellets of isosorbide-5-nitrate (IS-5-N) by assuming that the rate of release is of the first order. The residence times and transition-intensity functions of drug in the individual compartments have been estimated from the available data generated by the gamma scintigraphies of IS-5-N pellets labeled by 111 In . Based on these parameters, the total numbers of dissolved drug microspheres and their fluctuations at any instance have been calculated. The model is in accord with the existing in vivo dissolution data of the same drug independently obtained through plasma analysis. More important, the model predicts that fluctuations in terms of the standard deviations of the numbers of particles in the duodenum, jejunum, and ileum can be of the same orders of magnitude as the corresponding mean numbers when 100 microspheres are simultaneously administered orally; in practice, such fluctuations characterized by these deviations could result in an undesirable release profile. Discussion is given of the potential direct clinical application of the results obtained as well as the plausible indirect application of these results and the model derived to the analyses of chemical and biochemical reactors.

Determination of Imidacloprid and Triadimefon in White Pine by Gas Chromatography/Mass Spectrometry

Imidacloprid is one of a new class of highly systemic chloronicotinyl insecticides with significant activity against a wide range of insects. The triazole fungicides, triadimefon and triadimenol, are also systemic and highly effective in controlling a variety of economically important fungal diseases. A sensitive and reliable method for the determination of these compounds by GC/MS has been developed. Imidacloprid was converted to the heptafluorobutyryl derivative, whereas triadimefon and triadimenol were determined directly. Quantitation of all three analytes in white pine foliar extracts was performed in selected ion monitoring mode, by comparison with an external standard in sample matrix. Limits of quantitation were 0.01 ppm (10 pg injected) for imidacloprid and 0.1 ppm (100 pg injected) for both triadimefon and triadimenol. Overall mean recovery was 85.78 ± 5.20% (6.06%). This method has been successfully applied to quantify in-planta residues after treatment of white pine seedlings with a controlled-release pellet containing imidacloprid and triadimefon for control of white pine weevil and white pine blister rust, respectively. Mean recoveries for QC samples were 85.62 ± 9.34% (10.9%). Keywords: Imidacloprid; triadimefon; triadimenol; residue analysis; white pine

Evidence that ibuprofen antagonizes selective actions of estrogen and tamoxifen on rat bone.

Studies were performed to determine if the nonsteroidal anti-inflammatory drug ibuprofen alters bone and mineral metabolism in female rats. In experiment 1, four groups of growing rats underwent either sham operation or ovariectomy (OVX). One week later, controlled-release pellets with ibuprofen or placebo were implanted subcutaneously at the back of the neck. Following 3 weeks of treatment, rats were sacrificed and blood and bone samples were removed for serum assays and histomorphometric analysis. Body growth rate and the static cortical bone measurements made at the tibial diaphysis did not change in response to OVX. OVX, however, did increase radial bone growth, lowered serum 17beta-estradiol, reduced uterine weight, and decreased the cancellous bone area of the tibial metaphysis in the rats. Ibuprofen did not alter serum 17beta-estradiol or uterine weight but reduced radial bone growth as well as cancellous bone area of the tibial metaphysis in both sham-operated and OVX animals. In experiments 2 and 3, we tested the influence of ibuprofen on the effects of the tissue-selective estrogen agonist tamoxifen and of exogenous 17beta-estradiol in the OVX rat. Ibuprofen completely blocked the effects of tamoxifen and partially blocked the effects of 17beta-estradiol to prevent cancellous osteopenia. In contrast, ibuprofen did not influence the effects of tamoxifen and 17beta-estradiol to reduce radial bone growth. Besides the skeletal effects, ibuprofen suppressed estrogen-induced uterine growth. Our data suggest that ibuprofen blocks selective estrogen receptor-mediated activities in the rat.

The Imaging of a Controlled-Release Pellet Formulation Using Scanning Electron Microscopy—Potential for Artefact Generation

(1998). The Imaging of a Controlled-Release Pellet Formulation Using Scanning Electron Microscopy—Potential for Artefact Generation. Pharmaceutical Development and Technology: Vol. 3, No. 1, pp. 135-139.

Formulation and preparation of controlled release pellets of salbutamol by the air suspension technique

A controlled release preparation of salbutamol may improve patient compliance, minimise side effects and be valuable in the treatment of nocturnal asthma by extending drug action throughout the night. The aim of the study was therefore to formulate a controlled release pellet preparation of salbutamol via the air suspension technique. The study established that curing for 24 h at 38 ± 0.5°C was necessary for homogeneous film coats of Eudragit® RS30D and hence stable drug release characteristics. Pellets coated with 6% Eudragit® RS30D (polymer), 12.5% triethyl citrate (plasticiser) and 0.5% magnesium stearate (antitacki-ness agent) displayed desirable controlled drug release characteristics over the 8 h testing period. The manufacturing conditions employed in the study were shown to be reproducible thus ensuring reproducibility of drug release characteristics between batches of salbutamol controlled release pellets. Short term stability testing on the newly formulated pellets indicated no significant change in drug release characteristics relative to the initial drug release data when stored for 8 weeks at room temperature 20 ± 2°C or 37°C with 80% Relative Humidity or at low temperature (5 ± 1°C). However, pellets stored at 40°C showed a slower in-vitro drug release after 8 weeks of storage and therefore failed to maintain their initial drug release profile.