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Biomedical subjects

C T Rhodes

Publications and source records attributed to C T Rhodes.

At least 37 records · Page 2Linked to original sources
PubMed1994

The effect of process and formulation variables on the properties of spray-dried beta-galactosidase.

The objective of this study was to evaluate the joint effects of various processing and formulation variables on the properties of spray-dried beta-galactosidase using statistically designed experiments. The key response variables evaluated were product yield, residual enzymatic activity, moisture content and particle size and appearance. The residual enzymatic activity and product yield were significantly affected by the processing variables. The highest product yields were obtained when the drier outlet temperature was relatively high, resulting in extensive protein denaturation. Subsequent experiments, therefore, compared the relative effectiveness of four stabilizers (mannitol, sucrose, arginine hydrochloride and trehalose) in terms of their ability to preserve enzymatic activity during the spray-drying process and during long-term storage. Trehalose was the most suitable stabilizer. The effect of a number of other formulation variables (total solids level, ratio of stabilizer to protein, presence of surfactant and presence of buffer) was also investigated. A final formulation consisting of 6% beta-galactosidase and 10% trehalose in deionized water was selected. Spray-drying at inlet and outlet temperatures of 140 and 95 degrees C, respectively, results in greater than 70% yields of a fully active product with a moisture content of 2-5% and a mean particle size of 2-4 microns.

Arginine↗
PubMed1993

Stereochemical aspects of the molecular pharmaceutics of ibuprofen.

Thermal analysis, thermodynamics of solution and molecular modelling of (+)-ibuprofen and (+/-)-ibuprofen gave information on how heterochiral or homochiral interactions would affect the processing of ibuprofen. The study confirmed that (+/-)-ibuprofen exists as a true racemate with a 10% eutectic pure enantiomer composition. Both the racemate and the (+)-isomer crystal unit cells include four molecules and crystallize in the P2(1/c) and P2(1) space groups, respectively. Thus the intermolecular forces were different in each crystal. As a consequence the (+)-enantiomer lattice was more fragile but only slightly more soluble than the racemate in aqueous media. The solid-state structure contributions to solubility were different for the two crystals (delta H (+) = 51.1 and delta H(+/-) = 32.2 kJ mol-1) but the standard free energies of the solutions were comparable for both compounds.

Crystallization↗
PubMed1991

An evaluation of ibuprofen bioinversion by simulation.

Using a pharmacokinetic model recently proposed to explain ibuprofen disposition in man, plasma concentrations of pure ibuprofen enantiomers were simulated following oral administration of (-)-(R)-ibuprofen, (+)-(S)-ibuprofen, or rac-ibuprofen. Simulated and literature values for AUC's were used to compare S/R ratios for different cases of the model and for different methods of calculating the fraction of R bioinverted to S. Numerical simulation using STELLA confirmed previous results for different cases of bioinversion. Simulated S/R AUC ratios, for administration of the racemate, ranged from 4.0 (presystemic bioinversion) to 1.66 (systemic bioinversion). Literature values for S/R AUC ratios averaged 1.53 +/- 0.2 for administration of the racemate; therefore, systemic bioinversion was concluded to be representative of ibuprofen disposition. Additional simulations of S/R AUC ratios, for administration of (-)-(R)-ibuprofen only, ranged from 1.5 (presystemic bioinversion) to 0.66 (systemic bioinversion). Literature values for S/R AUC ratios averaged 0.50 +/- 0.9 for administration of (-)-(R)-ibuprofen only, which again supported conclusions of systemic bioinversion. Using different equations for estimation of fraction of R inverted to S (FR----S), results based on simulated data were identical; however, FR----S values based on literature data were different. Therefore, assumptions made for different FR----S equations do not appear to be rigorous. Calculations of FR----S, based on literature data, averaged 0.52 overall, indicating bioavailability of (+)-(S)-ibuprofen may be similar for a 150 mg dose of (+)-(S)-ibuprofen compared to a 200 mg dose of racemate.

Humans↗
PubMed1991

The design of analytical methods for use in topical epidermal growth factor product development.

Data from a reverse phase gradient elution HPLC assay for human epidermal growth factor (EGF) was compared and correlated with data obtained from a competitive heterogeneous radioimmunoassay (RIA). The RIA was established to measure very low concentrations of EGF in formulation drug release and compatibility studies. The HPLC assay, capable of resolving parent and possible modified or fragmented forms of EGF isolated from human urine, was studied as a potential development tool for stability and final product evaluation. As independent analytical methods, the HPLC and the RIA procedures produced correlated results when quantifying freshly prepared and certain degraded samples of EGF. The capacity of the HPLC method to serve as a stability indicating assay was examined. Degradation of EGF was induced by storage in 0.05 M phosphate buffer pH 7.4 at 25, 37 or 50 degrees C. The same three degradation products were detected at each temperature by the HPLC method, one of which was identified as L-isoaspartyl EGF.

Amino Acids↗
PubMed1991

Influence of different sources on the processing and biopharmaceutical properties of high-dose ibuprofen formulations.

It is known that depending on the manufacturing and synthetic processes, drugs may exist as different forms. As a result, physicochemical properties, compression characteristics, intrinsic dissolution and bioavailability may vary substantially. The purpose of this study was to investigate the effect of different sources of ibuprofen on the processing of tablets and on their properties. Another emphasis of this work was to rationalize one or several key characteristics of the raw material as directly related to wet granulation parameters and to the behavior of final tablets. Commercially available ibuprofen was obtained from different manufacturers and a preformulation program, including X-ray crystallography, differential scanning calorimetry, scanning electron microscopy, determination of particle size distribution and flowability, was performed to characterize the raw material. Granules were prepared with a planetary mixer and liquid requirements for the end point were obtained by monitoring power consumption. Tablets were manufactured on Stokes rotary and single punch instrumented presses. Data acquisition interfaces produced compression data for each formulation. Granules and final tablets were analyzed for hardness, dissolution profiles and content uniformity. Statistical evaluations using analysis of variance and multiple comparison procedures were performed on the results to determine the significance of the variability between independent parameters. The ibuprofen tested was found to be a unique polymorphic form with some differences in the external crystallinity. The particle size characteristics of the material also allowed a differentiation between sources and although there was no differences in dissolution patterns or content uniformity, particle size was found to account for 50% of the variability in tablet hardness. Two sources of ibuprofen with lower mean particle size showed significant variations in end point liquid requirements resulting in variable tablet crushing strength.

Biopharmaceutics↗
PubMed1991

Investigations of epidermal growth factor in semisolid formulations.

Three simple formulations, with various physicochemical characteristics, were designed as potential pharmaceutical bases for delivery of epidermal growth factor (EGF) to open wounds. The compatibility of EGF with formulation excipients and the release of EGF from each formulation were evaluated in vitro using a release cell apparatus. Samples were analyzed by competitive heterogeneous radioimmunoassay. The apparatus and procedures used in the study were validated to ensure EGF stability during the study, and to verify the absence of excipient interference with analytical procedure. Batches of Pluronic F-127 25% gel formulation and Carbopol gel formulation showed similar average EGF release rates of 17.12 and 16.55 micrograms/cm2/hr, respectively. A vanishing cream formulation similar to the commercial product Silvadene showed much slower release of 0.5 microgram/cm2/hr.

Chemistry, Pharmaceutical↗
PubMed1990

The development of USP dissolution and drug release standards.

Dissolution tests have been in use in the pharmaceutical industry for over 20 years, and they are official in The United States Pharmacopeia since the early 1960s. The dissolution test, reviewed primarily as a quality control tool, replaced the use of disintegration tests which had been official in The United States Pharmacopeia since 1950. Refinements in the dissolution test equipment and methodology have occurred over the years in order to enhance its relevance. The Subcommittees of the USP Committee of Revision dealing with these issues have developed and refined compendial dissolution standards and policies for conventional solid-oral dosage forms and modified-release dosage forms.

Delayed-Action Preparations↗
PubMed1990

Reversal of colchicine-induced mitotic arrest in Chinese hamster cells with a colchicine-specific monoclonal antibody.

The ability of a high-affinity colchicine-binding monoclonal antibody to reverse the effects of colchicine on Chinese hamster ovary cells was investigated. Using flow cytometry, a complete mitotic blockade was demonstrated after 16 hours with 2.5 x 10(-7) mol/l (molar) colchicine. Colchicine-induced changes were reversible when equimolar antibody was added simultaneously with or up to 6 hours after colchicine. With further delay in addition of antibody, a progressive irreversible increase in mitotic blockade and increase in mean cell size was observed. Prolonged colchicine exposure, without antibody reversal, led to polyploidy and structural chromosome breakage. Early antibody reversal restored cells to the diploid state, whereas delayed reversal resulted in a time-dependent increase in polyploidy. Colchicine-induced polyploidy and chromosomal aberrations may be the basis for both colchicine toxicity and the time-dependent increase in irreversibility of colchicine effects.

Animals↗
PubMed1989

Specific, high affinity colchicine binding monoclonal antibodies: development and characterization of the antibodies.

Nine colchicine specific monoclonal antibodies have been developed by immunizing BALB/c mice with a colchicine-keyhole limpet hemocyanin (Col-KLH) conjugate prepared using a bishydroxysuccinimide coupling reagent. Of four immunization procedures examined, intraperitoneal injection of the antigen attached to acid treated E. coli resulted in the maximum antigen specific antibody titers. A colchicine bovine serum albumin (Col-BSA) conjugate, prepared using a water soluble carbodiimide coupling technique, formed the basis of an enzyme linked immunosorbent assay used for screening hybridomas for colchicine specific antibody secretion and for determining the relative affinity and specificity profile of the monoclonal antibodies. All antibodies demonstrated high affinity, saturable binding to colchicine and low cross-reactivity with a panel of compounds structurally related to colchicine. The IC50 for the highest affinity antibody, C44, was 3.6 +/- 0.84 nM colchicine in the competitive enzyme immunoassay. The affinity of this antibody determined from Scatchard analysis of antibody binding to tritiated colchicine was 0.66 +/- 0.11 nM. Antibody C44 has the level of specificity and affinity suitable for a sensitive and selective immunoassay of colchicine for monitoring therapeutic drug levels. In addition, this antibody provides a specific pharmacologic antagonist for studies of colchicine's therapeutic mechanism and has the potential to reverse colchicine toxicity.

Animals↗
PubMed1989

Determination of thermodynamic parameters of complexation using a nonlinear regression method.

The new model and method introduced here allow the determination of more than one unknown from one set of raw experimental data. Even though the method was used to treat data from the complexation of phenytoin with cyclodextrins, the same approach could be exploited for other drug interaction systems. The method allows for a meaningful comparison of thermodynamic parameters for the interaction of either one drug with different cyclodextrins or one cyclodextrin with different drugs. The use of the approach could enhance the ability of the pharmaceutical scientist to analyze data from the solubility method to propose a rationale of interaction between drugs and complexing agents.

Chemistry, Pharmaceutical↗
PubMed1985

Studies of powder flow using a recording powder flowmeter and measurement of the dynamic angle of repose.

This paper describes the utility of the dynamic measurement of the angle of repose for pharmaceutical systems, using a variable rotating cylinder to quantify powder flow. The dynamic angle of repose of sodium chloride powder sieve fractions was evaluated using a variable rotating cylinder. The relationship between the static and the dynamic angle of repose is discussed. The dynamic angle of repose of six lots of a multivitamin preparation were compared for inter- and intralot variation. In both cases, no significant differences (p greater than 0.05) were observed. In the multivitamin formulation, lubricants at lower concentration levels did not show a significant effect (p greater than 0.05) on the dynamic angle of repose when compared with flow rates. The effect of different hopper sizes and geometry has been evaluated using the recording powder flowmeter. The results indicate that although different hoppers affect the quantitative nature of the results, the same general trends are apparent. Thus, it appears possible to use a recording powder flowmeter with small quantities of material to predict the effect of formulation and processing variables on the flow of production scale quantities. This paper does not describe a comprehensive evaluation of the pharmaceutical utility of measuring the dynamic angle of repose. However, the results discussed are not encouraging and suggest that the recording powder flowmeter is more sensitive to the effects of formulation and production variables on powder flow.

Chemistry, Pharmaceutical↗
PubMed1985

Effect of molecular structure variation on the disintegrant action of sodium starch glycolate.

The effect of variation in the degree of cross-linkage and extent of carboxymethylation on the disintegration and dissolution properties of sodium starch glycolate has been examined. Samples of sodium starch glycolate were evaluated for particle size distributions and bulk and tapped densities. The bulk powders were also tested for sedimentation volumes, water uptake, and bulk swelling. Direct compression formulations containing aspirin and hydrochlorothiazide and varying concentrations of the modified starches were tableted on a rotary tablet press and evaluated for weight variation, hardness, disintegration, and dissolution. The results indicate that relatively small changes in molecular structure can cause substantial modification of disintegrant properties and suggest that the specifications for one commercially available sodium starch glycolate are within optimal specifications for both cross-linkage and degree of substitution.

Aspirin↗