Good Sustained Release Properties Research Articles

In vitro and in vivo Studies of a New Sustained Release Formulation of Morphine

An in vivo preclinical study has been made of the oral absorption of morphine (CAS 57-27-2) from a new sustained release formulation (morphine-Eudragit L complex, MEC), which had shown good sustained release properties in in vitro dissolution studies. The absorption of morphine from capsules filled with morphine hydrochloride trihydrate (MHT) or MEC was compared in fasted and fed dogs. Mean plasma morphine concentrations obtained after administration of MHT and MEC to fasted dogs were similar, and no statistically significant differences were found in the pharmacokinetic parameters of morphine (Cmax, Tmax and area under the plasma morphine concentration versus time curve from time zero to the last time with a detectable concentration of morphine). When MHT and MEC were administered to fed animals, mean plasma morphine concentrations were again similar for both formulations, without statistically significant differences in the pharmacokinetic parameters of morphine. These results contrast with those obtained in vitro, and indicate the limited usefulness of in vitro assays for this kind of sustained release formulations in which pH and ionic strength are important factors for drug release from the polymeric structure. The plasma morphine concentrations obtained in fed dogs were generally lower than in fasted dogs, though they were detectable for a longer time, until 10 h after dosing, in contrast to up to 6 h in fasted dogs. It is postulated that the apparently prolonged absorption of morphine in fed dogs may be due to the enterohepatic recycling of the drug (excreted in bile as glucuronide, hydrolysed back to the parent compound in the intestine, and then reabsorbed) as a consequence of gallbladder emptying induced by food.

Sustained release properties of crosslinked and substituted starches

AbstractHigh amylose corn, waxy corn, and potato starches were crosslinked (XL) to an optimal degree and then substituted with carboxymethyl (CM) and aminoethyl (AE) groups, and their drug release properties, swelling power, and potential interactions with drugs were investigated. Propranolol hydrochloride, sodium diclofenac and acetaminophen were used as model drugs. High amylose starch required a higher XL degree to achieve good sustained release properties, whereas waxy corn required the least XL. Drug release was more governed by the matrix characteristics than by drug properties, and XL‐CM high amylose corn starch displayed a nearly constant drug release for all three drugs tested. Swelling power correlated well with sustained release properties with the better matrices swelling to greater extents. There was a potential interaction between XL‐AE‐starches and diclofenac as indicated by differential scanning calorimetry. Starches from different sources require different types and degrees of modifications to achieve satisfactory sustained release. © 2010 Wiley Periodicals, Inc. J Appl Polym Sci, 2010

Optimal synthesis of mesostructured hollow titania nanotubes templated on CaCO3 nanoparticles

Abstract Approximate 10 µm length of mesostructured hollow titania nanotubes with intact configuration was successfully prepared by using needle-like calcium carbonate and octadecylamine as double templates at room temperature in nonaqueous system. During the whole preparation, two parameters i.e. tetrabutoxytitanium/calcium carbonate molar ratio and annealing temperature, were optimized to obtain titania nanotubes with well-defined tubular morphology and mesoporous structure in tube walls. The as-prepared samples were characterized by scanning electron microscopy, transmission electron microscopy, broad-angle X-ray diffraction, pore size distribution and Brunauer–Emmett–Teller. The results showed that under optimal experimental conditions i.e. tetrabutoxytitanium/calcium carbonate molar ratio (50 wt.%) and annealing temperature (773 K), the tube materials exhibited uniform tubular structure with a length of 8–15 µm and an inner diameter of ∼ 400 nm, a wall thickness of ∼ 40 nm, a surface area of 112.2 m2/g and a pore volume of 0.18 cm3/g. The optimized titania nanotubes were utilized as a carrier for the immobilized of ibuprofen via a simple adsorption method. It was found that the loaded drug presented good sustained release property in three release media, i.e. simulated body fluid, normal saline and pure water.

Three-layered microcapsules as a long-term sustained release injection preparation

Three-layered milli-capsules (3LMC), diameter of 1.85 ± 0.07 and 0.15 ± 0.09 mm thickness, were designed for the long-term subcutaneous (sc) administration of drugs. 3LMCs composed of (1) surface membrane (release rate control membrane), (2) drug-carrying layer and (3) base membrane were prepared by dispensing each solution in series. As surface membrane, poly-(ɛ-caprolactone) having MW of 70 kDa (PCL70) was used in combination with plasticizer, polysorbate 60 (Tween60). Base membrane was prepared with PCL70. Fluorescein isothiocyanate labeled dextrans (FD-4, MW = 4 kDa and FD-20, MW = 20 kDa) were used as model drug and in vitro release experiment was performed with PCL70 surface membrane containing Tween60 with 0.3, 1.0 and 3.0% (w/w). As the amount of Tween60 increased, release rate of FD-4 was increased. PCL70 + 0.3% Tween60 membrane showed a good sustained release property for 5 weeks; 50.3 ± 6.0% of FD-4 was released during 5 weeks. When FD-20 was encapsulated, long-term sustained release was not obtained, 10.7 ± 3.6% was released during 5 weeks. However, when lower MW drug, leuprolide acetate, was encapsulated, 3LMC composed of PCL70 + 0.3% Tween60 showed a good sustained release property, 63.0 ± 5.9% released for 5 weeks. Leuprolide acetate encapsulated 3LMC was evaluated in rat experiment. After sc administration to rats, 0.5 and 1.0 mg, plasma leuprolide concentration showed its maximum concentration at day 1, thereafter gradually decreased and maintained the effective concentration for 14 weeks. Plasma leuprolide concentration vs. time curve showed a good dose-dependency. When surface membrane prepared by blending PCL70 and poly(lactic acid) (PLA) in the molar ratio of 5:1 was used, long-term sustained release property was not obtained. Instead, lower MW PCL, PCL40, was blended with PLA (5:1) to prepare surface membrane, sustained release of leuprolide was observed for 5 weeks. Through those studies, 3LMC has been shown to be a long-term sustained release preparation by properly selecting the surface membrane.

HPLC determination and pharmacokinetics of sustained-release bupropion tablets in dogs

The pharmacokinetics and bioequivalency of a newly developed sustained-release bupropion tablet was studied in six dogs after single oral administration and compared with a regular tablet (RT) in randomized two-period crossover design. A sensitive and rapid HPLC method was developed and validated for the quantitative determination of bupropion in dog plasma. The compound and the internal standard (I.S.) (hydroxyethylfludiazepam) were extracted from the plasma samples by liquid–liquid extraction. The extracts were analyzed by a reversed-phase HPLC with 50 mmol/l phosphate buffer (pH 5.5)–methanol (45:55, v/v) as the eluent. The assay was specific for bupropion. The calibration curves were linear in the range between 1 and 750 ng/ml. The validated lower limit of quantification was 1 ng/ml. The overall precision (expressed as R.S.D.) of quality controls were within 15%. The method was successfully applied to the bioequivalency study of bupropion in the two formulations. The C max of sustained-release tablet (ST) was significantly lower than that of the RT and the T max was significantly longer than that of the RT ( P<0.05). The relative bioavailability of the ST was (99.1±1.51)%, the results of ANOVA and two one sided tests indicated that the new ST exhibited good sustained release properties and was bioequivalent to the RT.

Poly( dl-lactic acid) as a direct compression excipient in controlled release tablets : Part I. Compaction behaviour and release characteristics of poly( dl-lactic acid) matrix tablets

High-molecular weight poly( dl-lactic acid) (PDLA, M v 85 000) was applied as a direct compression excipient in controlled release tablets. PDLA powders with good flowing properties were obtained by milling pre-cooled PDLA granules. Apparent yield pressure values ranged from 44 to 71 MPa for tabletting speeds of 0.033 and 300 mm/s, respectively, pointing to a high ductility and limited strain rate sensitivity. Tablets with good mechanical strength (tensile strength 2.5–3.7 MPa) were prepared at different compaction speeds. Dissolution experiments with different drugs showed that PDLA exhibited good sustained release properties. Initial tablet porosity, lubrication with magnesium stearate and pH of the dissolution medium hardly affected the release rate of the incorporated drug. Drug loads, however, markedly affected the release rate. For drug loads between 20 and 50% w/w, a constant fractional release rate was found. Upon further decreasing of the drug load, the release rate was found to increase. This remarkable finding was explained by the rapid and large increase of the pore volume of the tablets. The results show the unique properties of PDLA and its suitability to be applied as a direct compression and release controlling excipient in matrix tablets for oral drug administration.

Preparation and Evaluation of Sustained Release Ibuprofen Beads

AbstractSustained release beads of ibuprofen were prepared by a capillary method using cellulose acetate phthalate, surfactants (Tween 80 and Span 80), and polymers (K 100 M Methocel and K 100 LV Methocel). These beads were formulated into capsule and tablet dosage forms. The beads did not disintegrate in simulated gastric fluid; however, they disintegrated in simulated intestinal fluid. The dissolution profiles of ibuprofen beads and dosage forms of beads (tablets and capsules) were conducted in phosphate buffer (pH 7.2) at 37°C. The beads containing Span 80 and K 100 M Methocel resulted in prolonged drug release. The preparation containing Span 80 and equal quantities of both the polymers (K 100 M Methocel and K 100 LV Methocel), also showed good sustained release properties. The formulations prepared with Tween 80 and K 100 LV Methocel released over 90% of the drug in 2 hours indicating no sustained release properties. The beads in tablet dosage form yielded slower dissolution profiles compared to the beads in capsule form which, in turn, had slower release profiles compared to the beads alone. Release of ibuprofen was much slower from tablets after one year of storage compared to tablets immediately after their manufacture.

In vitro and in vivo evaluation of clarithromycin/poly(lactic acid) microspheres for intramuscular drug delivery

Clarithromycin is a macrolide antibiotic recommended for the treatment of upper respiratory tract infections. This report summarizes the results of in vitro and in vivo studies conducted to evaluate the feasibility of developing an intramuscular (i.m.) formulation of this compound by encapsulating in a biodegradable polymer, poly(lactic acid) (PLA). Drug/PLA microspheres were prepared by solvent evaporation and recovered by filtration or spray-drying. Variations in processing parameters, e.g., polymer concentration in the dispersed phase, type of continuous phase and the recovery process, did not appreciably alter microsphere particle shape, size or drug loading. In 0.05 M phosphate buffer (pH 7.4, at 37°C), compared to the dissolution of bulk drug, the microsphere formulations demonstrated good sustained release properties. In a preliminary in vivo study, 10 mg/kg drug was administered i.m. to groups of three dogs as a suspension of bulk drug or via PLA microspheres. Blood samples were collected over time to monitor drug and creatinine phosphokinase ( CPK ) concentrations. Both groups demonstrated drug concentrations ≥ 1 μg/ml for about 4 days after dosing. Also, the serum CPK concentrations in both groups were low, and compared well with those observed following the i.m. administration of placebo microspheres. The animals receiving drug/PLA microspheres demonstrated minor swelling at the site of injection which lasted for 12–24 h; however, the bulk drug treatment group exhibited much greater swelling lasting for 2–3 days. Since these observations do not correlate with serum CPK levels, alternative quantitative models are required to conclusively evaluate the potentials of microsphere formulations for the i.m. delivery of painful/irritating compounds like clarithromycin.

Food and a sustained release theophylline tablet on chronic dosing: bioavailability, peak-trough and trough-trough differences.

The bioavailability of theophylline and the serum concentration fluctuations after administration of a sustained release tablet (Theograd 250 mg, one tablet twice daily) were studied in the steady state in six volunteers. On postprandial administration of the 250 mg tablets the bioavailability was 89 +/- 16%. Good sustained release properties were obtained provided that the tablets were taken after a meal; Cmax was 7.9 +/- 2.0 mg X 1(-1), tmax was 5.3 +/- 1.6 h, the peak-trough difference was 2.3 +/- 0.6 mg X 1(-1) and the serum concentration fluctuation was accounted for 42.8 +/- 11.2%. It was shown that on postprandial administration the mean serum concentration-time profile could be successfully calculated by means of multiple dose projection from single dose data. However, when the a.m. dose was given on an empty stomach and the p.m. dose 3 h after a meal, it appeared not to be possible to use the single diurnal dose data for calculation of the steady state serum concentration-time profile: the experimentally observed a.m. trough levels were significantly higher than the p.m. trough values and also the observed mean serum concentration was significantly higher than the calculated level. The possible causes for this discrepancy are extensively discussed.