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Biomedical subjects

A Sakr

Publications and source records attributed to A Sakr.

At least 19 recordsLinked to original sources
PubMed2004

Poly(dimethylsiloxane) coatings for controlled drug release--polymer modifications.

Modifications of endhydroxylated poly(dimethylsiloxane) (PDMS) formulations were studied for their ability to be applied onto tablet cores in a spray-coating process and to control drug release in zero-order fashion. Modifications of the crosslinker from the most commonly used tetraethylorthosilicate (TEOS) to the trifunctional 3-(2,3-epoxypropoxy)propyltrimethoxysilane (SIG) and a 1:1 mixture of the two were undertaken. Addition of methylpolysiloxane-copolymers were studied. Lactose, microcrystalline cellulose (MCC) and polyethylene glycol 8000 (PEG) were the channeling agents applied. The effects on dispersion properties were characterized by particle size distribution and viscosity. Mechanical properties of resulting free films were studied to determine applicability in a pan-coating process. Release of hydrochlorothiazide (marker drug) was studied from tablets coated in a lab-size conventional coating pan. All dispersions were found suitable for a spray-coating process. Preparation of free films showed that copolymer addition was not possible due to great decline in mechanical properties. Tablets coated with formulations containing PEG were most suitable to control drug release, at only 5% coating weight. Constant release rates could be achieved for formulations with up to 25% PEG; higher amounts resulted in a non-linear release pattern. Upon adding 50% PEG, a drug release of 63% over 24 h could be achieved.

Cellulose↗
PubMed2003

Influence of methacrylic acid and hydroxypropylmethyl cellulose on the tablet properties and in vitro release of dextromethorphan hydrobromide.

The release of dextromethorphan hydrobromide from matrices containing hydroxypropylmethyl cellulose (HPMC K100LV) and methacrylic acid copolymer (Eudragit L100-55) has been evaluated at different ratios of the polymers. The physicochemical properties (including weight, thickness, crushing strengh, friability and disintegration time) were also determined at 1000, 2000 and 4000 p compression forces. No significant differences in weight uniformity and thickness values were observed between the different formulations. The crushing strength of the tablets increased with increasing compression force and it reached a constant level at 4000 p. The formulations containing only HPMC K100LV resulted in an extended release pattern, however, Eudragit L100-55 alone could not effectively prolong the drug release. A combination of HPMC K100LV and Eudragit L100-55 in a 1:1 ratio at the 40% level provided an almost similar drug release profile than the marketed product.

Acrylic Resins↗
PubMed2002

Effect of drug proportion and mixing time on the content uniformity of a low dose drug in a high shear mixer.

The purpose of this study was to investigate the effect of reducing drug proportion and mixing time on the content uniformity of a low dose drug. Buspirone hydrochloride was used as a model drug and was mixed with other ingredients in two different concentrations (0.5% w/w and 5% w/w) in a T. K. Fielder high shear mixer at a high impeller speed (522 rpm) and a high chopper speed (3600 rpm) up to 32 min. Samples were withdrawn from nine locations in the mixer at specific time points using a side-sampling thief probe. The final blends at 32 min were compressed using an instrumented tablet press. Tablets were sampled at the beginning, middle, and end of the compression run. The statistical results indicated that the drug proportion had a significant effect on the content uniformity of the powder blend and the corresponding tablets. For this study, the optimum time to mix the 0.5% w/w formulation was after 8 min while it was only 1 min for the 5% w/w formulation. The RSD of buspirone hydrochloride contents of tablets decreased as the compression run was toward its end. Uniformly mixed blends produced tablets that met the USP XXIV content uniformity requirements.

Analysis of Variance↗
PubMed2001

The effects of packaging on the stability of a moisture sensitive compound.

Packages that provided stability (less than a 10% loss in potency) of a moisture sensitive compound (PGE-7762928) in tablet form at accelerated conditions for 6 months were identified. The equilibrium moisture content of the tablets at 25 degrees C/60%RH, 30 degrees C/60%RH and 40 degrees C/75%RH were 2.3,2.4, and 2.9%, respectively. The tablet equilibrium moisture content, degradation rate of unpackaged product, and the moisture barrier properties of the packages were used to predict the stability of the packaged product. The physical and chemical stability (HPLC assay) of the products were measured after 2,4,6,8,12, and 24 weeks at ICH conditions. The Containers-Permeation(1) of polyvinyl chloride blisters, cyclic olefin blisters, aclar blisters, cold-form aluminum blisters was 0.259, 0.040, 0.008 and 0.001 mg per blister per day, respectively. At 6 months at 40 degrees C/75%RH, the percent active was 84% in polyvinyl chloride blisters, 91% in cyclic olefin blisters, 97% in aclar blisters, 100% in cold-form aluminum blisters and 99% in an high density polyethylene bottle with a foil induction seal. The stability results for the packaged product were fairly consistent with the predictions based on the moisture sensitivity of the product and the moisture barrier properties of the respective package. To gain a better prediction, the flux value determined by the Containers-Permeation procedure was adjusted for the internal moisture concentration of the blister.

Chemistry, Pharmaceutical↗
PubMed2001

Application of multiple response optimization technique to extended release formulations design.

The purpose of the present study was to apply response surface methodology and multiple response optimization utilizing superimposed contour diagrams to design extended release formulations with a preplanned release profile. Bumetanide solution was layered on sugar pellets followed by coating with various coating formulations according to a central composite statistical design using a Glatt GPCG 1 Wurster Fluid Bed. The coated pellets were tested for their release profiles and the percent of drug released after 1, 4 and 8 h were used to describe and optimize the release process. Statistical models describing the percent bumetanide released after 1, 4 and 8 h were developed and the corresponding contour diagrams were superimposed to predict the coating formulation parameters expected to produce target release profile. The pellets coated with the designed coating formulation were tested for their release profiles in comparison to the target profile. According to the model-independent approach using similarity factor (F2), the dissolution profile of the designed formulation and the expected target profile were found to be similar. It was concluded that response surface methodology and multiple response optimization could be successfully used to design and optimize extended release formulations with desired preplanned release profile.

Bumetanide↗
PubMed2001

Effect of anionic polymers on the release of propranolol hydrochloride from matrix tablets.

Anionic polymers, namely Eudragit S, Eudragit L 100-55, and sodium carboxymethylcellulose, were incorporated into hydroxypropylmethylcellulose (HPMC K100M) to modify the drug release from HPMC matrices. The effects of changing the ratio of HPMC to anionic polymers were examined in water and in media with different pH. The dissolution profiles were compared according to release rates. The interaction between propranolol hydrochloride and anionic polymers was confirmed using the UV difference spectra method. The drug release was controlled with the type of anionic polymer and the interaction between propranolol hydrochloride and anionic polymers. The HPMC-anionic polymer ratio also influenced the drug release. The matrix containing HPMC-Eudragit L 100-55 (1:1 ratio) produced pH-independent extended-release tablets in water, 0.1 N HCl, and pH 6.8 phosphate buffer.

Acrylic Resins↗
PubMed2001

A severe genotype with favourable outcome in very long chain acyl-CoA dehydrogenase deficiency.

A patient with very long chain acyl-CoA dehydrogenase (VLCAD) deficiency is reported. He had a severe neonatal presentation and cardiomyopathy. He was found to be homozygous for a severe mutation with no residual enzyme activity. Tandem mass spectrometry on dried blood spots revealed increased long chain acylcarnitines. VLCAD enzyme activity was severely decreased to 2% of control levels. Dietary management consisted of skimmed milk supplemented with medium chain triglycerides and L-carnitine. Outcome was good and there was no acute recurrence.

Acyl-CoA Dehydrogenase, Long-Chain↗
PubMed2001

Pharmacokinetics of buspirone extended-release tablets: a single-dose study.

The objective of this study is to evaluate the absorption of buspirone and its biotransformation to 1-(2-pyrimidinyl) piperazine (1-PP) from two different extended-release (ER) formulations of buspirone HCl tablets (12-hour and 24-hour in vitro release) and from a commercially available immediate-release (IR) tablet. A single dose of the 30 mg ER tablets was compared with two doses of the 15 mg IR tablet administered 12 hours apart. Eighteen healthy male subjects participated in this randomized, open-label, three-treatment crossover study. Blood samples were obtained at 22 time points from predose (0 hour) until 36 hours postdose, and plasma concentration of buspirone and 1-PP was determined by LC/tandem mass spectrometry method. The pharmacokinetic parameters AUC0-t, AUC0-infinity, Cmax, tmax, Ke, and t1/2 were calculated and statistically analyzed. The results indicated extended release of buspirone from the two test products in vivo with a 70% to 90% greater bioavailability in comparison with the IR formulation. The bioavailability of 1-PP from ER formulations appears to be equal to that from the IR formulation. Both buspirone ER tablets successfully delivered bioavailable buspirone with a reduction in peak drug and metabolite plasma levels, prolonged buspirone plasma concentrations, and decreased ratio of 1-PP to buspirone concentration with less intersubject variation when evaluated as a single-dose study in healthy human subjects.

Administration, Oral↗
PubMed2001

A comparative multidose pharmacokinetic study of buspirone extended-release tablets with a reference immediate-release product.

Buspirone is disclosed in U.S. Patent No. 3,717,634 as a pharmaceutically active compound that has been found to be effective for the treatment of anxiety disorders and depression. In this randomized, two-treatment, two-period, multidose crossover study, the pharmacokinetics of a once-daily extended-release (ER)formulation of buspirone was compared with that of an immediate-release (IR) formulation of commercially available buspirone. A total of 30 mg of the ER formulation was administered to 36 healthy volunteers once daily for 7 days, and 15 mg of the IR formulation was administered twice daily for 7 days. Pharmacokinetic profiles of buspirone and its metabolite, 1-pyrimidinylpiperazine (1-PP), were obtained at steady state. The bioavailability of buspirone from the ER formulation was more than three times higher than that from the IR formulation at steady state, and that of 1-PP was about 25% less. The mean steady-state Cmax of buspirone from the ER formulation was 46% higher than that from the IR formulation (p < 0.05), and that for 1-PP was lower by 29% (p < 0.05). The mean apparent half-life of buspirone from the ER formulation (9.04 hours) was considerably longer than that observed for the IR formulation (3.06 hours). The median 1-PP/buspirone AUC ratio was much higher for the IR formulation at steady state (24.4) than for the ER formulation (6.44). There were no significant differences in average pharmacokinetic metrics observed in men and women. Based on these observations of the potential benefits of once-daily dosing with the ER product in terms of prolonged buspirone plasma concentrations, a significant increase in the ratio of buspirone to 1-PP concentration with a lower intersubject variation could be achieved that should provide an improvement in the desired therapeutic effects of buspirone.

Anti-Anxiety Agents↗
PubMed2000

Predicting dissolution via hydrodynamics: salicylic acid tablets in flow through cell dissolution.

A model was established for the dissolution of non-disintegrating salicylic acid tablets as a function of hydrodynamic conditions in the Flow Through Cell system (USP Apparatus 4). The approach was to model the dissolution rate of the material as a function of the Reynold's number, the dimensionless engineering term that describes the degree of turbulence. The dissolution rate of USP calibrator salicylic acid tablets was measured as a function of tablet size, orientation within the cell, dissolution media flow rate, and cell size. All of these variables were found to have an effect on dissolution rate, consistent with theory. An equation to predict this dissolution was established as: N(SH)=-21.1+12.6xN(RE)(0.5), R(2)=0.99; 10<N(re)<292.

Models, Theoretical↗
PubMed2000

Liquid chromatographic method for the analysis of buspirone HCl and its potential impurities.

An accurate, reproducible, and sensitive method for the determination of buspirone HCl and its potential impurities is developed and validated. The validated liquid chromaography method is conducted to meet the Food and Drug Administration/ International Conference on Harmonization requirements for the analysis of buspirone HCI in the presence of its impurities. Five buspirone HCI potential impurities, including 1-(2-pyrimidinyl)-piperazine (I), propargyl chloride (II), 3,3'-tetramethylene glutarimide (III), propargyl glutarimide (IV), and the Mannich base-condensate of I-IV fumarate (V), are separated using a microBondapack C18 column by gradient elution with a flow rate 2.0 mL/min. The initial mobile phase composition is 90:10 (v/v) 10mM KH2PO4 (pH 6.1)-acetonitrile. After a 1-min initial hold, a linear gradient is performed in 26 min to 35:65 (v/v) 10mM KH2PO4 (pH 6.1)-acetonitrile. The samples are detected at 210 and 240 nm using a photo-diode array detector. The linear range of detection for buspirone HCI was between 1.25 ng/microL and 500 ng/microL, with a limit of quantification of 1.25 ng/microL. The linearity, range, peak purity, selectivity, system performance parameters, precision, accuracy, and robustness for all of the impurities were also shown to have acceptable values.

Buspirone↗
PubMed1999

Modeling of a roller-compaction process using neural networks and genetic algorithms.

In this study, roller-compaction of acetaminophene was studied to model the effect of binder type (hydroxypropyl methyl cellulose (HPMC), polyethylene glycol (PEG), Carbopol), binder concentration (5, 10 and 20%), number of roller-compaction passes (one or two), and extragranular microcrystalline cellulose addition on the properties of compressed tablets. Forty-two batches resulted from the experimental design. The artificial neural network methodology (ANN) along with genetic algorithms were used for data analysis and optimization. ANN and genetic models provided R2 values between 0.3593 and 0.9991 for measured responses. When a set of validation experiments was analyzed, genetic algorithm predictions of tablet characteristics were much better than the ANN. Optimization based on genetic algorithm showed that using HPMC at 20%, with two roller-compaction passes would produce mechanically acceptable acetaminophene tablets. PEG and carbopol would also produce acceptable tablets perhaps more suitable for sustained release applications. Using PEG as a binder had the additional advantage of not requiring an external lubricant during tablet manufacturing.

Acetaminophen↗
PubMed1999

Stability-indicating high-performance liquid chromatographic assay of buspirone HCl.

The United States Pharmacopoeia high-performance liquid chromatographic (HPLC) assay method of buspirone is not able to discriminate buspirone from its degradation products. The purpose of this work is to develop a sensitive, selective, and validated stability-indicating HPLC assay for the analysis of a buspirone hydrochloride in a bulk drug. Buspirone HCI and its potential impurities and degradation products are analyzed on an Ultrasphere C18 column heated to 40 degrees C using a gradient program that contains monobasic potassium phosphate buffer solution (pH 6.9) and acetonitrile-methanol mixture (13:17) of 35% for 5 minutes, then increased to 54% in 5.5 minutes. The samples are monitored using a photo-diode array detector and integrated at 244 and 210 nm. The stress testing of buspirone HCI shows that buspirone acid hydrochloride is the major degradation product. The developed method shows a separation of buspirone degradation product and its potential impurities in one run. The stability of buspirone HCI is studied under accelerated conditions in order to provide a rapid indication of differences that might result from a change in the manufacturing process or source of the sample. The forced degradation conditions include the effect of heat, moisture, light, acid-base hydrolysis, sonication, and oxidation. The compatibility of buspirone HCI with some pharmaceutical excipients is studied under stress conditions. The linear range of buspirone HCI is between 5 and 200 ng/microL with a limit of quantitation of 2.5 ng/microL. The intraassay percentage deviation is not more than 0.38%, and the day-to-day variation was not more than 0.80%. The selectivity, repeatability, linearity, range, accuracy, sample solution stability, ruggedness, and robustness show acceptable values.

Buspirone↗
PubMed1994

Development and evaluation of a monolithic floating dosage form for furosemide.

The poor bioavailability of orally dosed furosemide (60%), a weakly acidic drug, is due to the presence of a biological window comprised of the upper gastrointestinal tract. The purpose of the present study was to develop and optimize in vitro a monolithic modified-release dosage form (MMR) for furosemide with increased gastric residence time and to evaluate the in vivo performance of the dosage form. The principle of floatation was used to restrict the MMR to the stomach. A two-factor three-level full factorial experimental design was employed for formulation development. A flow-through cell was designed to evaluate in vitro dissolution parameters. Quadratic regression models indicated the polymer viscosity and polymer:drug ratio to be significant (p < 0.05) formulation factors in determining the duration of buoyancy and the release profile. Statistical optimization using response surface methodology with certain physiological constraints relating to gastric emptying time predicted an optimal MMR. In vivo evaluation of the optimized MMR in beagle dogs resulted in a significant increase (p < 0.05) in the absolute bioavailability for the MMR dosage form (42.9%) as compared to the commercially available tablet (33.4%) and enteric product (29.5%). Significant in vitro/in vivo correlations (p < 0.05) were obtained for the MMR using deconvolution analysis normalized for bioavailability. The floating dosage form was found to be a feasible approach in delivering furosemide to the upper gastrointestinal tract to maximize drug absorption.

Animals↗
PubMed1994

Influence of pH and plasticizers on drug release from ethylcellulose pseudolatex coated pellets.

Six potential plasticizers for an ethylcellulose (EC) pseudolatex coating system (Aquacoat) were evaluated at three levels (25, 30, and 35%) to study the influence of these additives on the release of a model compound, propranolol hydrochloride, from pellets in two different media, dilute HCl and phosphate buffer, pH 7.4. For the majority of the plasticizers, the release rate decreased when larger amounts of plasticizer were incorporated into the coating. However, for the plasticizers dibutyl sebacate and dibutyl adipate, no further reduction in the release rate was observed following dissolution testing in dilute HCl when the level of plasticizer was increased from 30 to 35%. This suggests that the saturation capacity of these plasticizers in the film coating had been exceeded. The media pH was found to influence the dissolution characteristics of the coatings. Faster release rates as well as earlier curve inflection points and T50% values were observed for plasticizers evaluated in phosphate buffer. All plasticizers used were independent of pH. Correlation of the dissolution results with properties of free films indicated that slower release (more complete film formation) is associated with softer and weaker films with greater elongation.

Buffers↗
PubMed1994

Characterization of esterase and alcohol dehydrogenase activity in skin. Metabolism of retinyl palmitate to retinol (vitamin A) during percutaneous absorption.

Retinyl palmitate, a widely used ingredient in cosmetic products, is promoted for its beneficial effects on the appearance of skin. Previous studies suggest that enzymes are available in skin to metabolize this ingredient during skin absorption. Esterase activity hydrolyzes retinyl palmitate to retinol (vitamin A), which is oxidized in many tissues to retinoic acid primarily by alcohol dehydrogenase. The activities of esterase and alcohol dehydrogenase were characterized in hairless guinea pig skin by using flow-through diffusion cells and radiolabeled model compounds (methyl salicylate and benzyl alcohol) previously shown to be metabolized by these enzymes. Methyl salicylate was hydrolyzed by esterase to a greater extent in viable skin than in nonviable skin. Glycine conjugation of salicylic acid and benzoic acid occurred only in viable skin. The metabolism of methyl salicylate and benzyl alcohol occurred to a greater extent in male guinea pig skin than in female guinea pig skin. The percutaneous absorption of both radiolabeled compounds was similar in viable and nonviable skin. About 30 and 18% of topically applied retinyl palmitate were absorbed from an acetone vehicle by hairless guinea pig skin and human skin, respectively. Less than 1% of the applied dose of this lipophilic compound diffused from skin into the receptor fluid. Retinol was the only detectable metabolite of retinyl palmitate in both hairless guinea pig and human skin. In human skin, 44% of the absorbed retinyl palmitate was hydrolyzed to retinol. The use of retinyl palmitate in cosmetic formulations may result in significant delivery of retinol into the skin.

Alcohol Dehydrogenase↗
PubMed1994

Processing considerations for an EC latex coating system: influence of curing time and temperature.

The influence of curing time and curing temperature for a commercially available ethylcellulose latex coating dispersion (Aquacoat) were evaluated using response surface methodology. Levels for the factor curing time ranged from 30 to 300 minutes while levels for curing temperature ranged from 45 degrees to 75 degrees C. Responses, A, kappa, and gamma, were derived from regression analysis of the dissolution profiles and correspond to the maximum amount of drug released over the 12 hour sampling period, the rate of release, and the inflection point of the dissolution profile, respectively. The nature of the response surface was dramatically influenced by the plasticizer incorporated into the coating formula. When dibutyl sebacate was employed as the plasticizer, faster release resulted (higher A and kappa values, lower gamma values) when samples were exposed to higher curing temperatures or were stored for longer periods of time. Paradoxically, when tributyl citrate was used as the plasticizer, slower release resulted when samples were exposed to more rigorous conditions. Overall, curing temperature had a more dramatic effect than curing time.

Cellulose↗