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Biomedical subjects

J B Schwartz

Publications and source records attributed to J B Schwartz.

At least 19 recordsLinked to original sources
PubMed2001

Thermodynamic analysis of compact formation; compaction, unloading, and ejection. II. Mechanical energy (work) and thermal energy (heat) determinations of compact unloading and ejection.

A compaction calorimeter, previously described (DeCrosta, M.T., Schwartz, J.B., Wigent, J.B., Marshall, K., 2000. Thermodynamic analysis of compact formation; compaction, unloading, and ejection. I. Design and development of a compaction calorimeter and mechanical and thermal energy determinations of powder compaction. Int. J. Pharm. 198, 113--134), was utilized to evaluate the thermodynamics of the unloading and ejection of compacts of Avicel pH102, Emcompress, Fast-Flo #316, Starch 1500, and acetaminophen (APAP). A constant strain waveform, applied by a compaction simulator, enabled the separate thermodynamic evaluation of unloading from compaction. The brittle materials, Fast-Flo #316 and Emcompress, displayed the most unloading work, and the plastic/self-lubricating materials, Avicel and Starch 1500, displayed the least. Unloading heat values were negative for all materials, except APAP. APAP's positive heat values indicated the breaking of bonds during unloading as a result of its highly elastic nature. Positive internal energy changes of unloading, which indicate the net breaking of bonds, were observed for APAP and Emcompress over the compaction forces tested. Negative energy changes for Starch 1500, Fast-Flo #316, and Avicel became positive with increasing compaction forces. Ejection work increased with increasing compaction force for the brittle materials, whereas smaller ejection work values for Avicel, Starch 1500, and APAP remained constant. Increasing negative heat values as a function of compaction force were observed for Fast-Flo #316 and Emcompress. Negative internal energy values for ejection were observed for Fast-Flo #316 and Emcompress, which indicates net bond formation as a result of high shear of the compact with the die wall. Internal energy changes for Starch 1500, Avicel, and APAP, were approximately zero, indicating the absence of net bonding or bond formation during the process.

Algorithms↗
PubMed2001

Effects of age and gender on the QT response to exercise.

Although gender differences in resting corrected QT intervals have been well documented, the effects of age and exercise on gender differences in QT have not been well characterized. Data were analyzed from 91 healthy volunteers (47 women). Forty-five young subjects (aged 20 to 39 years) and 46 older subjects (61 to 84 years) were recruited. All underwent Bruce protocol stress testing. QT offset and QT peak were measured at exercise stages and during recovery. In a heart rate (HR)-independent analysis, data were divided into HR bins of 10 beats/min. In a HR-dependent analysis, 6 models were used to approximate the QT-RR relation; the best were used to analyze age and gender effects. Women had longer QT intervals than men at a HR < 100 beats/min for QT offset and < 110 beats/min for QT peak. At faster HRs, no significant differences were found. Older subjects had slightly longer QT intervals than the younger group, with a mean difference of 2 ms for QT offset and 9 ms for QT peak. Women had increased constant and slope coefficients. The QT increase in the elderly was relatively small. Gender differences in QT disappear at faster HRs, whereas age differences are smaller but are present throughout exercise, with no significant age-gender interaction. A natural logarithmic model provides the best approximation of the QT-RR relation with exercise, is simple to implement, and should become the preferred method of QT correction.

Adult↗
PubMed2001

Antimicrobial and diffusional correlation of N-alkyl betaines and N-alkyl-N,N-dimethylamine oxides from semisolids.

Previous studies have shown that two classes of amphoteric surfactants, N-alkyl betaines and N-alkyl-N,N-dimethylamine oxides, exhibit pronounced antimicrobial activity in combination and have potential for use in a semisolid formulation for topical or vaginal delivery. In this work, several potential delivery systems were prepared and evaluated for antimicrobial activity and diffusional properties. A novel antimicrobial test for semisolids was proposed that determined the contact time needed to kill microorganisms. The unformulated agents in solution exhibited the faster kill within 60 min, followed by the hydroxyethylcellulose gel formulation in 90 min, and the poloxamer gel and a cream that required several hours. Diffusion from the dosage form utilized a Slide-A-Lyzer diffusion cassette with a 10,000 MWCO membrane with (14)C-labeled active species added to the aforementioned antimicrobial formulations. Diffusion of the individual betaine and amine oxide derivatives were tracked over time to determine the diffusion rates and profiles of the components in each formulation and in solution. The betaine derivative diffused up to three times faster than the amine oxide derivative within the first 2 h, but the amount diffused was approximately equivalent at 24 h. The formulations delayed release in the same rank order as the contact time kill analysis: hydroxyethylcellulose gel > poloxamer gel > cream.

Anti-Bacterial Agents↗
PubMed2001

Use of a moist granulation technique (MGT) to develop controlled-release dosage forms of acetaminophen.

The moist granulation technique (MGT), which involves agglomeration and moisture absorption, has only been applied to immediate-release dosage forms. Our results indicate that MGT appears to be applicable in developing a controlled-release formulation. A small amount of granulating fluid (water) was added to a powder blend to activate a dry binder (such as polyvinylpyrrolidone [PVP] at 2% and 3.6%) and to facilitate agglomeration. Then, a moisture-absorbing material (microcrystalline cellulose [MCC]) was added to absorb any excess moisture. By adding MCC in this way, a drying step was not necessary. Acetaminophen (APAP) was the model drug, with diluents lactose FastFlo and dicalcium phosphate. Hydroxypropylcellulose (HPC) was used as the controlled-release agent. The MGT was compared to conventional wet granulation (WG) and direct compression (DC) processing methods. The results indicate that MGT appears to be applicable in developing a controlled-release formulation. Particle size distribution of MGT and WG batches containing 3.6% PVP is similar.

Absorption↗
PubMed2001

The effects of formulation factors on the moist granulation technique for controlled-release tablets.

Controlled-release tablets were prepared by the moist granulation technique (MGT), a granulating method that uses very limited amounts of liquid and requires microcrystalline cellulose (MCC) to absorb moisture. Acetaminophen (APAP) was the model drug, and the polymer hydroxypropylcellulose (HPC) served as the controlled-release agent. The effects of varying drug, binder (polyvinylpyrrolidone, PVP), polymer, and MCC levels on granule properties and tablet dissolution were studied. Dissolution testing was carried out in distilled water using the USP paddle method. In all cases, the granules flowed and compressed well. The granule properties were evaluated by calculating the mean particle size for all batches from sieve analysis data. The results indicate that MGT can be applied to control drug release, and at a polymer content of 44.6% or more, the process is robust enough to allow slight variations in formulation factors without affecting drug release.

Acetaminophen↗
PubMed2001

A novel method for measuring gel strength of controlled release hydrogel tablets using a cone/plate rheometer.

A novel method for measuring gel strength of hydrogel controlled release (CR) tablets is presented. CR tablets containing hydroxypropyl methylcellulose (HPMC) were fixed to a glass plate, placed in a dissolution apparatus, and subjected to dissolution conditions corresponding to 50% drug release. Tablets were then removed from the dissolution apparatus without disturbing the swollen (gel) layer. Tablet gel strength (gamma) was determined by shearing the external gelled layer of the tablet by a cone/plate rheometer recording E, energy/volume, as a function of rotational speed of the cone, RPM. The RPM is increased to the point of "Shear Failure," RPMsf, i.e., until there is no further increase in E. Plots of E vs. RPM were fit to a bi-exponential equation, where epsilon is the zero RPM intercept of the plot. gamma is calculated from gamma = ERPMsf - epsilon. gamma is defined as the minimum energy input/unit volume needed to cause shear failure of the tablet gel layer. Mean gamma for tablets containing 50% theophylline and different ratios of HPMC to Fast Flo lactose were determined. Tablets containing 30%, 15%, and 8% HPMC K100MP have gamma means of 6600, 4700, and 1500 ergs/cm3, and percent relative standard deviations of 9, 13, 33%, respectively. Tablets made entirely of HPMC K100MP (no theophylline or lactose) have an gamma of 15,500 ergs/cm3. gamma values are significantly different (p < 0.0001) between the various formulations. gamma values also show a strong inverse correlation with the cumulative percent of drug released in vitro. Results obtained demonstrate the application of this novel method for measuring gel strength of different CR hydrogel tablets and using this strength to characterize drug diffusion in vitro.

Bronchodilator Agents↗
PubMed2001

Effect of processing methods and heat treatment on the formation of wax matrix tablets for sustained drug release.

The objective of this study was to evaluate the effects of processing methods and heat treatment on matrix formation and subsequent drug release from wax matrix tablets for controlled release. Phenylpropanolamine hydrochloride (PPA) and Compritol were processed with appropriate diluent(s) using either dry blending (DB), wet granulation (WG), partial melt granulation (PMG), or melt granulation (MG). Then the tablets were heat-treated at 80 degrees C. Particle size distribution and compressibility, along with drug release, tablet micro-morphology, wettability, porosity, and tortuosity were investigated. The drug release was different for the four processing methods even though the tablet formulation was identical. Heat treatment further retarded drug release and its effect was related to the previous manufacturing processes. Scanning Electron Microscopy (SEM) showed that heat treatment redistributed the wax and formed a film-like structure covering drug and excipients. The contact angle of tablets made from DB, WG, and PMG methods increased after heat treatment, while that of tablets made from MG remained constant. Tablet tortuosity calculated from drug release rate constants increased dramatically after heat treatment. Drug release from the wax tablets with or without heat treatment was best described by the Higuchi equation. Different processing methods produced different matrix structures that resulted in different drug release rates. Heat treatment retarded drug release mainly by increasing tortuosity of the matrix. Contact angle measurement and SEM analysis indicated that heat treatment caused the wax to melt, redistribute, coat the drug and diluents, and form a network structure.

Delayed-Action Preparations↗
PubMed2001

The effect of formulation composition and dissolution parameters on the gel strength of controlled release hydrogel tablets.

The impact of hydrogel polymers and dissolution media on tablet gel strength, Gamma, of controlled release (CR) hydrogel tablets was investigated. CR tablets containing either hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), or carbomer were formulated with theophylline and Fast Flo lactose, to produce tablets with a polymer content of 8, 15, and 30% w/w. Gamma was measured using a previously reported method. The drug dissolution profiles were similar, irrespective of polymer type or dissolution media (DI water, 0.1 N HCl, and pH 6.8 phosphate buffer), at the same % w/w level of polymer. Gamma, however, showed large and significant differences (p < or = 0.05) between tablets containing different polymers and between different dissolution media. Gamma values were HPMC KI00MP > HPC HXF > carbomer 971P (same % w/w) with absolute Gamma values at 30% w/w in DI water of 6600, 4600, and 1600 ergs/cm3, respectively. Gamma for HPMC based tablets was independent of changes in dissolution media, while the Gamma values for HPC tablets were 18% lower in acid and buffer than in DI water. Of the polymers tested, carbomer based tablets had the lowest Gamma values in all dissolution media and an unexpected 58% lower Gamma in buffer compared with DI water or acid. Gamma provides a quantitative measure of the effect of formulation and dissolution parameter changes on tablet gel layer strength, under in vitro stress conditions that may parallel in vivo tablet performance, but which cannot be deduced from a comparison of dissolution profiles or polymer viscosity.

Chemistry, Pharmaceutical↗
PubMed2001

Race but not age affects erythromycin breath test results in older hypertensive men.

Erythromycin breath tests (ERBT) were performed to determine age and racial effects on CYP3A4-mediated hepatic clearance in hypertensive men (n = 43) in the clinical setting. Older hypertensive African American men (n = 19: 71 +/- 8 years, mean +/- SD) had faster ERBT clearance compared with Caucasian (n = 20: 72 +/- 6 years) hypertensive men (at 20 minutes after dosing: 0.042 +/- 0.01 percent dose/min exhaled vs. 0.033 +/- 0.013; at 60 minutes after dosing: 0.030 +/- 0.05 vs. 0.023 +/- 0.007 percent dose/min exhaled; ANOVA, p = 0.007), while age, smoking, and reported alcohol intake did not affect ERBT. The data suggest faster hepatic CYP3A-mediated clearance in African American men compared with Caucasian men, and that race may significantly affect CYP3A-mediated hepatic clearance in patients treated for hypertension.

Age Factors↗
PubMed2001

Diffuse idiopathic skeletal hyperostosis causes artificially elevated lumbar bone mineral density measured by dual X-ray absorptiometry.

A 76-yr-old man with bilateral total hip arthroplasties was referred for a baseline bone mineral density (BMD) measurement. The L1-L4 lumbar bone density revealed a density above the upper expected value for a young individual (i.e., T-score > 2.5) with large intervertebral variation, while the forearm study revealed an osteoporotic measurement. Lumbar spine radiographs demonstrated abundant, flowing ossification of the anterior spinal ligament, predominantly at L3, consistent with diffuse idiopathic skeletal hyperostosis, which accounted for the increased BMD.

Absorptiometry, Photon↗
PubMed2001

Vitamin intake, recommended intake, and gender differences.

The role of vitamins in promoting good health and preventing disease is currently gaining recognition. Daily iron and folate intake should be higher in menstruating women than in men of similar age, while lower total intake of vitamins A, B, E, K, and zinc are based on body size, and recommendations are usually lower in women compared to men. Adequate daily intake can be achieved through a balanced diet for most nutrients and vitamins. Exceptions are the need for supplementation of most vitamins and folate in pregnant women and for vitamin D and calcium in older individuals.

Female↗
PubMed2001

The evaluation of pharmacologic therapy in humans: a brief summary of the drug evaluation process and guidelines for clinical trials as they related to women.

Significant progress has been made in including women in clinical and drug evaluation trials. Nonetheless, for most drugs currently on the market, analysis of benefits by sex is not available. At least some of the adverse effects of newer drugs in women could be due to the lack of inclusion in studies from which therapeutic regimens were derived. The data currently available on potential sex differences in pharmacokinetics and pharmacodynamics are also limited by having been obtained from healthy subjects receiving only one medication in studies designed only to detect moderate-to-large (> 30-50%) differences between the sexes. The clinical environment is different: patients consume multiple medications, including over-the-counter medications as well as nutraceuticals and dietary supplements; patients are, on average, older than healthy volunteers or even patients enrolled in investigational studies; and patients are more likely to have multiple diseases. In addition, adequate numbers of women still have not been enrolled in clinical trials for the therapy of many common disorders. The prudent clinician will remember that every time a therapy is initiated for an individual patient, especially a female patient, it is a clinical trial and the outcome is uncertain.

Clinical Trials as Topic↗
PubMed2000

Thermodynamic analysis of compact formation; compaction, unloading, and ejection. I. Design and development of a compaction calorimeter and mechanical and thermal energy determinations of powder compaction.

The aim of this investigation was to determine and evaluate the thermodynamic properties, i.e. heat, work, and internal energy change, of the compaction process by developing a 'Compaction Calorimeter'. Compaction of common excipients and acetaminophen was performed by a double-ended, constant-strain tableting waveform utilizing an instrumented 'Compaction Simulator.' A constant-strain waveform provides a specific quantity of applied compaction work. A calorimeter, built around the dies, used a metal oxide thermistor to measure the temperature of the system. A resolution of 0.0001 degrees C with a sampling time of 5 s was used to monitor the temperature. An aluminum die within a plastic insulating die, in conjunction with fiberglass punches, comprised the calorimeter. Mechanical (work) and thermal (heat) calibrations of the elastic punch deformation were performed. An energy correction method was outlined to account for system heat effects and mechanical work of the punches. Compaction simulator transducers measured upper and lower punch forces and displacements. Measurements of the effective heat capacity of the samples were performed utilizing an electrical resistance heater. Specific heat capacities of the samples were determined by differential scanning calorimetry. The calibration techniques were utilized to determine heat, work, and the change in internal energies of powder compaction. Future publications will address the thermodynamic evaluation of the tablet sub-processes of unloading and ejection.

Calibration↗
PubMed2000

Race and sex influence clearance of nifedipine: results of a population study.

OBJECTIVE: To estimate oral clearance of nifedipine and to determine demographic and clinical covariates that affect nifedipine clearance in a clinical population. METHODS: Apparent oral clearance of nifedipine and protein binding were measured in 226 patients receiving sustained-release nifedipine formulations for hypertension and coronary artery disease (black men, n = 111; black women, n = 27; white men, n = 64; white women, n = 24). Mean age +/- SD was 71 +/- 11 years, and mean weight was 86 +/- 17 kg. Nifedipine concentrations were analyzed by HPLC, protein binding was measured by equilibrium dialysis, clearance and covariate effects were estimated by a nonlinear mixed effects population model, and statistical analyses were performed by a nonlinear mixed-effects model (clearance) and ANOVA (protein binding). RESULTS: Clearance was significantly slower in black subjects (8.9 +/- 0.7 mL/min/kg; mean +/- SE) compared with white subjects (11.6 +/- 0.8 mL/min/kg; P = .00004) and in men compared with women (9.3 +/- 0.6 versus 12.1 +/- 1.5 mL/min/kg; P = .0021). Reported alcohol use (alcohol, 8.6 +/- 1.1 versus no alcohol, 10.8 +/- 0.6 mL/min/kg; P = .0002) and smoking status (smoker, 8.8 +/- 2.0 versus nonsmoker, 10.2 +/- 0.6 mL/min/kg; P = .0362) also affected nifedipine clearance. Race and sex had no effect on protein binding of nifedipine (P = .29 and P = .44, respectively). No effects of age, stable coronary artery disease, or reported intake of beta-blockers on nifedipine clearance were detected in this primarily elderly population with hypertension. CONCLUSIONS: The data suggest that race, sex, and environmental factors are identifiable sources of interindividual variation in the oral clearance of nifedipine, a CYP3A substrate. Our experience also suggests that data from clinical populations may be biased with regard to age, sex, and formulation selection, and covariates may not be independently distributed, which can limit analyses.

Aged↗
PubMed2000

Faster clearance of sustained release verapamil in men versus women: continuing observations on sex-specific differences after oral administration of verapamil.

Pharmacokinetic studies after administration of 120 mg oral sustained- and regular-release racemic verapamil were performed in 13 healthy subjects (seven men, age 74 +/- 4 years [mean +/- SD], weight 69.9 +/- 5.4 kg, and body mass index 24.6 +/- 2.2]; and six women, age 65 +/- 13 years, weight 65 +/- 9.9 kg, and body mass index 25.3 +/- 3). Verapamil was measured by HPLC, concentration versus time data analyzed by noncompartmental models, and statistical analyses performed by ANOVA for repeated measurements. The area under the concentration versus time curve (AUC) after administration of sustained-release verapamil was 48,951 +/- 18,079 ng/mL x min(-1) in women compared with 25,595 +/- 10,245 in men and lower than after administration of regular-release verapamil (63,055 +/- 24,411 for women and 34,686 +/- 25,279 in men; P = .05 for sex-related effect and P < .02 for formulation effect). AUC ratios of norverapamil (N-demethylated metabolite) to verapamil after administration of sustained-release verapamil were 1.43 +/- 0.26 in women compared with 1.74 +/- 0.41 in men and 1.43 +/- 0.26 in women compared with 1.78 +/- 0.37 in men after administration of regular-release verapamil (P = .1 for sex-related effect and P = .9 for formulation effect). Apparent oral clearance was 43 +/- 15 mL/min/kg in women compared with 75 +/- 29 in men after administration of sustained-release verapamil and 35 +/- 16 mL/min/kg in women compared with 65 +/- 31 in men after administration of regular-release verapamil (P < .05 for sex-related effect and P < .02 for formulation effect). Apparent oral clearance of both regular- and sustained-release formulations of verapamil was faster in men compared with women in contrast to findings after intravenous administration of verapamil, suggesting that intestinal processes are a factor in sex-specific difference in drug clearance. Greater verapamil and norverapamil bioavailability after administration of regular- compared with sustained-release verapamil also suggests saturable processes at the intestinal level.

Administration, Oral↗
PubMed2000

Effect of diluents on tablet integrity and controlled drug release.

The objective of this study was to evaluate the effect of diluents and wax level on tablet integrity during heat treatment and dissolution for sustained-release formulations and the resultant effect on drug release. Dibasic calcium phosphate dihydrate (DCPD), microcrystalline cellulose (MCC), and lactose were evaluated for their effect on tablet integrity during drug dissolution and heat treatment in wax matrix formulations. A newly developed direct compression diluent, dibasic calcium phosphate anhydrous (DCPA), was also evaluated. Compritol 888 ATO was used as the wax matrix material, with phenylpropanolamine hydrochloride (PPA) as a model drug. Tablets were made by direct compression and then subjected to heat treatment at 80 degrees C for 30 min. The results showed that MCC, lactose, and DCPA could maintain tablets intact during heat treatment above the melting point of wax (70 degrees C-75 degrees C). However, DCPD tablets showed wax egress during the treatment. MCC tablets swelled and cracked during drug dissolution and resulted in quick release. DCPD and lactose tablets remained intact during dissolution and gave slower release than MCC tablets. DCPA tablets without heat treatment disintegrated very quickly and showed immediate release. In contrast, heat-treated DCPA tablets remained intact through the 24-hr dissolution test and only released about 80% PPA at 6 hr. In the investigation of wax level, DCPD was used as the diluent. The drug release rate decreased as the wax content increased from 15% to 81.25%. The dissolution data were best described by the Higuchi square-root-of-time model. Diluents showed various effects during heat treatment and drug dissolution. The integrity of the tablets was related to the drug release rate. Heat treatment retarded drug release if there was no wax egress.

Calcium Phosphates↗