Response surface methodology to obtain naproxen controlled release tablets from its microspheres with Eudragit L100-55

PURPOSE: Naproxen CR tablets have been obtained from its microspheres prepared by coprecipitation with Eudragit L100-55. The purpose of this work was to evaluate the main and interaction effects of deaggregating agent concentration (X1), compression pressure (X2) and amount of precipitating water (X3) on naproxen release. A secondary purpose was to obtain an optimized naproxen controlled release solid oral dosage form with a predictable 12 h drug release. METHOD: Eudragit L100-55 (10 g) was dissolved in 100 ml of ethyl alcohol, and 30g of naproxen was dispersed in it with stirring. Purified water (100mL, cooled to 4 degrees C) containing calcium chloride as a deaggregating agent was added to an alcoholic solution and homogenized. The mixture was filtered to obtain microspheres. Drug content analysis was performed spectrophotometrically at 332 nm. Tablets were prepared by compressing microspheres containing 500mg of naproxen after adding 1% magnesium stearate. Dissolution was performed by the USP specifications of naproxen tablets. A 3-factor 3-level Box-Behnken design was employed to get 15 experimental runs. The independent variables used were X1, X2 and X3. The dependent variables were dissolution at different time points with constraints on yield value and angle of repose of the microspheres, and hardness and thickness of the tablets. The dissolution constraints were placed such that the naproxen is released for 12 h by Higuchi's square root of time kinetics. RESULTS: The mathematical relationship obtained between X1, X2, X3 and the cumulative per cent of naproxen dissolved in 12 h with various constraints (Y5) was Y5 = 92.39 - 1.13X1 - 4.84X2 - 2.12X3 - 2.26X1X2 - 0.5X1X3 - 0.4X2X3 + 2.4X(1)(2) - 0.4X(2)(2) (R2 = 0.9). The equation shows that X1, X2 and X3 affected the release inversely, and the most significant interaction was between X1 and X2. Y5 has been maximized for optimization of naproxen release. CONCLUSIONS: Controlled release tablets of naproxen with predictable drug release characteristics were obtained by compressing its microspheres with Eudragit L100-55.     

1H-NMR detectable fatty acyl chain unsaturation in excised leiomyosarcoma correlate with grade and mitotic activity.

We report on the use of 1H-NMR two-dimensional total correlated spectroscopy (2D TOCSY) at 600 MHz for an ex vivo analysis of fatty acyl chain lipid in normal smooth muscle and a series of primary retroperitoneal leiomyosarcomas. These TOCSY spectra were used to identify and quantitate the methylene protons situated between unsaturated site protons (D) to those bordered by only one unsaturated site proton (C). The D/C cross-peak volume ratios determined for oleic (18:1), linoleic (18:2), linolenic (18:3), and arachidonic (20:4) acids were 0.0, 1.3, 2.7, and 4.0, respectively, suggesting that this ratio can be a measure of the degree of unsaturation for fatty acyl chains of lipids. The D/C cross-peak volume ratio was found to be proportional to the mean mitotic activity (r = 0.94) in nine smooth muscle tissues. These results suggest, that for leiomyosarcoma, the degree of fatty acyl unsaturation may be an important determinant of the metastatic potential of these tumors. Furthermore, application of TOCSY for the ex vivo study of smooth muscle tumors would potentially serve as a pathologist-independent and quantitative method for assessment of leiomyosarcoma grade and mitotic activity thereby rendering a more accurate staging of patients.     

Evidence for Layer-Specific Connectional Heterogeneity in the Mouse Auditory Corticocollicular System

The auditory cortex (AC) sends long-range projections to virtually all subcortical auditory structures. One of the largest and most complex of these—the projection between AC and inferior colliculus (IC; the corticocollicular pathway)—originates from layer 5 and deep layer 6. Though previous work has shown that these two corticocollicular projection systems have different physiological properties and network connectivities, their functional organization is poorly understood. Here, using a combination of traditional and viral tracers combined with in vivo imaging in both sexes of the mouse, we observed that layer 5 and layer 6 corticocollicular neurons differ in their areas of origin and termination patterns. Layer 5 corticocollicular neurons are concentrated in primary AC, while layer 6 corticocollicular neurons emanate from broad auditory and limbic areas in the temporal cortex. In addition, layer 5 sends dense projections of both small and large (>1 µm² area) terminals to all regions of nonlemniscal IC, while layer 6 sends small terminals to the most superficial 50–100 µm of the IC. These findings suggest that layer 5 and 6 corticocollicular projections are optimized to play distinct roles in corticofugal modulation. Layer 5 neurons provide strong, rapid, and unimodal feedback to the nonlemniscal IC, while layer 6 neurons provide heteromodal and limbic modulation diffusely to the nonlemniscal IC. Such organizational diversity in the corticocollicular pathway may help to explain the heterogeneous effects of corticocollicular manipulations and, given similar diversity in corticothalamic pathways, may be a general principle in top-down modulation.SIGNIFICANCE STATEMENT We demonstrate that a major descending system in the brain is actually two systems. That is, the auditory corticocollicular projection, which exerts considerable influence over the midbrain, comprises two projections: one from layer 5 and the other from layer 6. The layer 6 projection is diffusely organized, receives multisensory inputs, and ends in small terminals; while the layer 5 projection is derived from a circumscribed auditory cortical area and ends in large terminals. These data suggest that the varied effects of cortical manipulations on the midbrain may be related to effects on two disparate systems. These findings have broader implications because other descending systems derive from two layers. Therefore, a duplex organization may be a common motif in descending control.     

Controlled release multiparticulate beads coated with starch acetate: material characterization, and identification of critical formulation and process variables

The objectives of the present investigation were to prepare and characterize starch acetate (SA) with high degree of substitution (dS) and to study its prospect as film-forming agent in a controlled-release multiparticulate drug delivery system. As a part of the development process by quality by design, the objectives also included identification of critical formulation and process variables that affect the release of a drug. SA, a relatively new polymer, was characterized because it showed good film-forming properties. SA with dS 2.9 was synthesized from corn starch by paste disruption technique. It was compared with the raw material, starch, by Fourier transform infrared spectroscopy, X-ray diffraction, and molecular mass analysis. Viscosity of SA solution increased logarithmically with the polymer concentration. At higher polymer concentrations (1.5-5.0%), the solutions showed pseudoplastic behavior. Among the plasticizers tested, triacetin and triethyl citrate yielded free films with acceptable mechanical properties. The glass transition temperature (Tg) of the films could be well controlled by these plasticizers. Unplasticized film showed a Tg of 31.8 degrees C. A trend was found that increase in triacetin concentration in SA films resulted in increase in permeability coefficient for tritiated water. Scanning electron microscopic photographs showed a clear and smooth plasticized film compared to rough unplasticized film. Dyphylline-loaded beads were coated with highly substituted SA to evaluate the main effects of the formulation and process variables on the release of the drug and to figure out the reliability of the screening design. A seven-factor, twelve-run Plackett-Burman screening design was used. The response variables were cumulative percent of drug released in 0.5, 1, 4, 8, and 12 hr. Quantitative evaluation of the design revealed that coating weight gain, plasticizer concentration, and post-drying temperature had greater influence on the drug release than the others. The main effects on drug release after 12 hr decreased in the following order: coating weight gain (-7.81), plasticizer concentration (4.96), postdrying temperature (-2.51), SA concentration (-0.80), inlet temperature (0.51), postdrying time (-0.31), and atomizing pressure (-0.28).     

Imidazopyridine-Based Fatty Acid Synthase Inhibitors That Show Anti-HCV Activity and in Vivo Target Modulation

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Design, in vitro stability, and ocular hypotensive activity of t-butalone chemical delivery systems

The objective of this work was to synthesize two bioreversible diacyl derivatives of t-butalone (chemical delivery systems), determine their chemical and in vitro stability, and investigate their potential use as topical antiglaucoma agents. The stability of these compounds was determined in isotonic phosphate buffers (pH range 5-8) and in selected biological media, including human whole blood, rabbit and rat blood, and the anterior segment tissues of rabbit. The ocular hypotensive activity of these compounds in unrestrained, normotensive albino rabbits was determined with a pneumatonometer. The two compounds were stable at lower pH. The stability decreased as the pH increased, suggesting their lability to base-catalyzed hydrolysis. These compounds exhibited significant differences in the hydrolytic rates in the whole blood among species examined (rat > rabbit > human). The observed rates of disappearance in different ocular tissues were indicative of relative enzyme activity in these media (iris-ciliary body > cornea > aqueous humor). The two compounds exhibited a significant ocular hypotensive activity (P < 0.01) at 2% dose level. The peak activity was found between 2 and 4 h, and the activity was maintained for 4.5 to 7 h. The dipivalyl derivative of t-butalone exhibited more pronounced decrease in intraocular pressure than that of diisovaleryl derivative. The present study suggests the possible use of diacyl derivatives of t-butalone as ocular hypotensive agents.     

Long-term stability characterization of a controlled release gastrointestinal therapeutic system coated with a cellulose acetate pseudolatex

The objective of the present study was to study the long term effects of storage of osmotically controlled gastrointestinal therapeutic system (GITS) in exaggerated conditions of temperature and humidity. Bilayered osmotic tablets were obtained with atenolol, Polyox N80, Carbopol 934P and magnesium stearate in one layer, and Polyox 303, Carbopol 974, sodium chloride and magnesium stearate in the other layer. A customized cellulose acetate (CA) pseudolatex was used to provide semipermeable housing around the tablet and an orifice was drilled into the drug layer to obtain the Atenolol GITS. The GITS were stored at 4 degrees C (refrigeration), 25 degrees C, 37 degrees C, 45 degrees C, 55 degrees C, 37 degrees C/11% RH, 37 degrees C/51% RH, and 37 degrees C/91% RH. Quantitative X-ray diffraction and dissolution studies were performed at regular intervals for one year. Aqueous CA polymeric film formation continued in GITS stored at higher temperature by gradual evaporation of moisture and coalescence of polymer. At lower temperatures atenolol crystallinity increased with time, but at higher temperatures the crystallinity was decreased. At higher humidity, a decrease in crystallinity was observed. A decrease in dissolution rate and extent was observed at higher temperature and higher humidity conditions. Exaggerated temperature and humidity conditions affected the dissolution profile by modifying the CA pseudolatex membrane and crystallinity of atenolol.     

Controlled Release Multiparticulate Beads Coated with Starch Acetate: Material Characterization,and Identification of Critical Formulation and Process Variables

The objectives of the present investigation were to prepare and characterize starch acetate (SA) with high degree of substitution (dS) and to study its prospect as film-forming agent in a controlled-release multiparticulate drug delivery system. As a part of the development process by quality by design, the objectives also included identification of critical formulation and process variables that affect the release of a drug. SA, a relatively new polymer, was characterized because it showed good film-forming properties. SA with dS 2.9 was synthesized from corn starch by paste disruption technique. It was compared with the raw material, starch, by Fourier transform infrared spectroscopy, X-ray diffraction, and molecular mass analysis. Viscosity of SA solution increased logarithmically with the polymer concentration. At higher polymer concentrations (1.5–5.0%), the solutions showed pseudoplastic behavior. Among the plasticizers tested, triacetin and triethyl citrate yielded free films with acceptable mechanical properties. The glass transition temperature (T_g) of the films could be well controlled by these plasticizers. Unplasticized film showed a T_g of 31.8°C. A trend was found that increase in triacetin concentration in SA films resulted in increase in permeability coefficient for tritiated water. Scanning electron microscopic photographs showed a clear and smooth plasticized film compared to rough unplasticized film. Dyphylline-loaded beads were coated with highly substituted SA to evaluate the main effects of the formulation and process variables on the release of the drug and to figure out the reliability of the screening design. A seven-factor, twelve-run Plackett-Burman screening design was used. The response variables were cumulative percent of drug released in 0.5, 1, 4, 8, and 12 hr. Quantitative evaluation of the design revealed that coating weight gain, plasticizer concentration, and post-drying temperature had greater influence on the drug release than the others. The main effects on drug release after 12 hr decreased in the following order: coating weight gain (?7.81), plasticizer concentration (4.96), postdrying temperature (?2.51), SA concentration (?0.80), inlet temperature (0.51), postdrying time (?0.31), and atomizing pressure (?0.28).