George Zografi: researcher and educator.
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Chemistry, Pharmaceutical↗
Biomedical subjects
Paul M Bummer
Publications and source records attributed to Paul M Bummer.
Mass transport properties of progesterone and estradiol in model microemulsion formulations.
PURPOSE: The purpose of these studies was to determine the extent to which drug loading influences the mass transport characteristics of poorly soluble steroids from model microemulsion formulations in vitro. METHODS: Two conditions of drug loading in the microemulsions were tested, "near saturation" and "constant loaded." Mass flux of (3)H-labelled progesterone or estradiol was measured in a side-by-side diffusion chamber from microemulsions consisting of Brij 97, Miglyol 812 and water. Pulsed gradient NMR was used to measure the diffusivities of all components. The thermodynamic activity and fraction of free drug in the formulations were measured by polymer uptake. Solute flux was calculated employing an aqueous boundary layer model. RESULTS: Under near saturation loading, all microemulsion formulations showed significantly increased flux of steroids compared to the saturated aqueous solution. For both steroids flux values in the 0.5 and 1% systems were significantly lower for the 3% oil formulation, despite the observation that the 3% formulation held significantly more drug. On the other hand, for all the formulations under constant drug loading, solute flux was only moderately increased for progesterone and not at all for estradiol when compared to the saturated aqueous solution. Under both loading conditions, thermodynamic activities did not correlate to flux indicating some other factor was modulating mass transport. Effective diffusivities of the steroids in formulations as determined by NMR were significantly reduced compared to those of the monomer drug in aqueous solution. In both near-saturated and constant-loaded conditions, the calculated values for progesterone flux were markedly similar to those observed experimentally suggesting solubilization and diffusion events in the aqueous boundary layer had a strong influence on mass transport. In contrast, calculations for estradiol were less successful in modeling the observed flux values. CONCLUSIONS: In systems nearly saturated with drug, the microemulsion formulation leads to a greatly enhanced rate of steady-state mass transport while in systems with drug loading far from saturation, the microemulsion formulation appears to have a minimal ability to promote mass transport. The aqueous boundary layer diffusion model was successful in fitting progesterone results but was not successful for estradiol.
Algorithms↗
Interaction of a partially fluorinated long-chain nicotinate with dipalmitoylphosphatidylcholine.
The interaction of a partially fluorinated long-chain nicotinate, F-NA18, a compound of interest as a chemopreventive agent, with dipalmitoylphosphatidylcholine (DPPC) was investigated in monolayers at the air-water interface and in fully hydrated bilayers and compared with its hydrocarbon analog, NA18. For the monolayer studies, the compression isotherms of mixtures of F-NA18 with DPPC were recorded at various compositions on a hydrochloric acid subphase (pH = 1.9-2.1, 32 +/- 2 degrees C). Analysis of the composition dependence of the average molecular area at constant film pressure and of the dependence of the breakpoints of the phase transitions suggests that F-NA18 is miscible with DPPC at the air-water interface, whereas NA18 shows some degree of immiscibility. In differential scanning calorimetry studies, only one major phase transition was observed for F-NA18-DPPC mixtures, whereas NA18-DPPC mixtures exhibited a complex phase behavior. The differences in the phase behavior of the respective mixtures may be the result of the geometric packing constraints of F-NA18 versus NA18. Therefore, for biomedical applications, the use of a partially fluorinated tail may offer advantages over simple hydrocarbon systems because, in addition to the chain length, the position and degree of fluorination can be adjusted.
1,2-Dipalmitoylphosphatidylcholine↗
Mixing behavior of 10-(perfluorohexyl)-decanol and DPPC.
Fluorocarbon alcohol such as 10-(perfluorohexyl)-decanol are of interest for novel pulmonary drug delivery approaches. The purpose of this study was to investigate the mixing behavior of 10-(perfluorohexyl)-decanol with dipalmitoylphosphatidylcholine (DPPC), the major component of lung surfactant as an aid in assessing usefulness for this and other biomedical applications. The impact of 10-(perfluorohexyl)-decanol on the phase transitions of DPPC bilayers fully hydrated with a 0.15 M sodium chloride solution were studied using differential scanning calorimetry (DSC). No peak corresponding to excess alcohol was observed. The fluorinated alcohol caused DPPC peak broadening, especially below X(DPPC) < 0.95, and elimination of the pretransition of DPPC at X(DPPC) approximately 0.91. The onset of the main phase transition remains constant down to X(DPPC) approximately 0.91, suggesting limited miscibility in the gel phase. Hydration of the 10-(perfluorohexyl)-decanol-DPPC mixtures with calcium chloride (2 mM) in place of sodium chloride did not alter the macroscopic phase behavior. In addition to the thermal properties, the miscibility of 10-(perfluorohexyl)-decanol in DPPC in monolayers at the air water interface was investigated on water, sodium chloride (0.15 M), calcium chloride (2 mM) or hydrochloric acid (pH 1.9) subphases. The concentration dependence of the onset pressure of the liquid-expanded to liquid condensed phase transition of DPPC showed a slight change with increasing mole fraction on all four subphases. The surface area-mole fraction diagrams of 10-(perfluorohexyl)-decanol and DPPC on water, sodium chloride and calcium chloride showed near ideal behavior with slight negative deviations at higher surface pressure. A more significant negative deviation was observed for the hydrochloric acid subphase. Overall, both the DSC and the monolayer studies suggest that 10-(perfluorohexyl)-decanol and DPPC are partially miscible in biological mono- and bilayers. The macroscopic phase behavior 10-(perfluorohexyl)-decanol-DPPC system is significantly different from the analogous hydrocarbon system, which is attributed to a less favorable packing of the partially fluorinated hydrophobic tails in the mono- and bilayer.
1,2-Dipalmitoylphosphatidylcholine↗
Interaction of long-chain nicotinates with dipalmitoylphosphatidylcholine.
The interaction of four long-chain nicotinates, compounds that are of interest as potential chemopreventive agents, with dipalmitoylphosphatidylcholine (DPPC) was investigated in monolayers at the air-water interface and in fully hydrated bilayers. For the monolayer studies, the compression isotherms of mixtures of the respective nicotinate with DPPC were recorded at various compositions on a hydrochloric acid subphase (pH 1.9-2.1, 37 +/- 2 degrees C). The headgroup of the nicotinates (24-29 A2/molecule) is larger than that of the hydrophobic tail (20 A2/molecule). The pure nicotinates exhibit a temperature- and chain length-dependent transition from an expanded to a condensed phase. Analysis of the concentration dependence of the average molecular area at constant film pressure and the concentration dependence of the breakpoint of the phase transition from the expanded to the condensed state suggests that all four DPPC-nicotinate mixtures are partially miscible at the air-water interface. Although a complex phase behavior with several phase transitions was observed, differential scanning calorimetry studies of the four mixtures are also indicative of the partial miscibility of DPPC and the respective nicotinate. Overall, the complex phase behavior most likely results from the head-tail mismatch of the nicotinates and the geometric packing constraints in the two-component lipid bilayer.
1,2-Dipalmitoylphosphatidylcholine↗
Physical chemical considerations of lipid-based oral drug delivery--solid lipid nanoparticles.
Of all the methods employed by formulators when presented with the task of improving oral bioavailability, the use of lipid assemblies is perhaps the least understood. Nonetheless, lipid-based formulations, and in particular solid lipid nanoparticles (SLN), show great promise for enhancing the oral bioavailability of some of the most poorly absorbed compounds. The physical/chemical characteristics of lipid-based systems are highly complex because of the existence of a variety of lipid assembly morphologies, the morphology-dependent solubility of drug, the interconversion of assembly morphology as a function of time and chemical structure, and the simultaneous lipid digestion. The present work will center on recent studies of the relevant physicochemical characteristics of SLN, most notably solubility of the drug in the lipid matrix, location of the drug in the aggregate, drug release properties of the aggregate, and particle size stability. Strengths and weaknesses of the lipid assemblies, in particular solid lipid nanoparticles, in promoting drug delivery by the oral route for systemic or Peyer's patch uptake will be highlighted, and possible future research pathways will be suggested.
Administration, Oral↗
Chemical stability of esters of nicotinic acid intended for pulmonary administration by liquid ventilation.
PURPOSE: It has been suggested that fluorocarbon liquid may be a unique vehicle for the delivery of drugs directly to the acutely injured lung. A prodrug approach was used as a means of enhancing the solubility of a model drug (nicotinic acid) in the fluorocarbon. The solubility, the chemical stability of the putative prodrugs, and the sensitivity to enzymatic hydrolysis was investigated. METHODS: The solubility of each nicotinic acid ester was determined in buffer as a function of pH and in perflubron. The octanol/buffer partition coefficient was determined at pH 7.4. The chemical stability of the putative prodrugs was determined as a function of pH, temperature, buffer content, and ionic strength. In addition, sensitivity of the esters to enzymatic degradation was evaluated. RESULTS: Compared with nicotinic acid, the solubility in perflubron of the esters was significantly enhanced. In aqueous buffers, the esters exhibited pseudo-first order degradation kinetics, with both acid and base catalyzed loss. Studies of the fluorobutyl ester indicate quantitative loss of the putative prodrug and release of the parent nicotinic acid. Porcine esterase accelerated the loss of fluorobutyl ester by a factor of over 200 compared with chemical hydrolysis at pH 7.4. CONCLUSIONS: The properties of the fluorinated esters suggest that they may be suitable candidates for further testing as possible prodrugs of nicotinic acid based upon higher solubility in perflubron, rapid release of the parent drug after simple hydrolysis, and sensitivity to the presence of a model esterase enzyme.
Algorithms↗
Kinetics of paclitaxel 2'-N-methylpyridinium mesylate decomposition.
This study was designed to examine the kinetics of decomposition of paclitaxel 2'-N-methylpyridinium mesylate (PNMM), a derivative of paclitaxel. Further, the potential for PNMM to act as a prodrug of paclitaxel was assessed in vitro. Stability studies of PNMM were conducted over a pH range of 4.0 to 8.0 at 25 degrees C. The critical micelle concentration (CMC) of PNMM was determined by pulsating bubble surfactometry. Studies of the conversion of PNMM to paclitaxel were conducted in vitro in human plasma. Decomposition of PNMM followed apparent zero-order kinetics. The pH-rate profile exhibited no evidence of acid catalysis down to pH 4.0, while the rate was accelerated under base conditions. Surface tension studies suggested that PNMM formed micelles with a CMC of approximately 34 micro g/mL. Conversion studies in phosphate buffer showed that no more than 5% of PNMM converted to paclitaxel, while in human plasma the conversion was about 25%. The degradation of PNMM was via apparent zero-order kinetics and was dependent upon pH. The observed apparent zero-order kinetics of decomposition of PNMM was consistent with the formation of micelles in phosphate buffer. In buffered aqueous media alone or in human plasma, PNMM did not convert quantitatively to paclitaxel. Thus, the limiting factor in the application of PNMM as a prodrug would appear to be the poor potential to convert to paclitaxel.
Antineoplastic Agents↗
Coprecipitation of nonoxynol-9 with polyvinylpyrrolidone to decrease vaginal irritation potential while maintaining spermicidal potency.
The aim of this study was to test the hypothesis that polyvinylpyrrolidone (PVP) would increase the critical micelle concentration (CMC) of nonoxynol-9 (N-9), providing a reduction in its irritation potential, while maintaining essential spermicidal activity. Solid coprecipitates of N-9 with PVP were manufactured with the use of a modified lyophilization process. The irritation potential of N-9 was estimated by an in vitro assay, monitoring the extent of hemolysis of red blood cells. CMCs of N-9 were measured in the presence of various concentrations of PVP. A modified Sander-Cramer assay was implemented to measure the spermicidal activity of N-9 and the N-9/PVP coprecipitates. With the use of the lyophilization process and more suitable solvents, solid coprecipitates of N-9/PVP were manufactured with no residual organic solvents. The irritation potential of N-9 was reduced when in the presence of PVP-50% hemolysis values increased from 0.054 mM to more than 0.2mM. N-9 CMC values increased in the presence of PVP from 0.085 mM (0% PVP) to 0.110 mM (3.5% PVP) and 0.16 6mM (10% PVP). However, spermicidal activities ranged from 0.213 mM to 0.238 mM, N-9 remaining steady regardless of the amount of PVP. By use of N-9/PVP coprecipitates, the self-association properties and irritation potentials of N-9 were altered. This result suggests a process to produce a spermicidal product that reduces the detrimental implications to the vaginal epithelium while maintaining the essential spermicidal activity.
Animals↗
Mixing of partially fluorinated carboxylic acids with their hydrocarbon analogs at the air-water interface.
The mixing behavior of 1-(perfluorobutyl)undecanoic acid-pentadecanoic acid (C15), 1-(perfluorohexyl)undecanoic acid-heptadecanoic acid (C17), and 1-(perfluorooctyl) undecanoic acid-nonadecanoic acid (C19) mixtures was investigated at the air-water interface. The compression isotherms of the fluorocarbon acid-hydrocarbon acid mixtures were recorded at various compositions on hydrochloric acid (pH 1.9, 37+/-2 degrees C) as a subphase. The phase transition, limiting molecular area, area at collapse pressure, and collapse pressure were determined for all pi-A isotherms. The mixing behavior was assessed by analyzing the concentration dependence of the average molecular area at constant film pressure (area/mole fraction or A-X diagram) and the concentration dependence of the phase transition, where possible. All three acid mixtures show a negative deviation from ideal behavior at surface pressures between 5 and 20 mN/m, which is indicative of an attractive interaction of both compounds in the mixed monolayer at the air-water interface. The miscibility apparently decreases with increasing chain length of the carboxylic acids (C15>C17>C19).
Air↗
Characterization and validation of the gamma-scintigraphic method for determining liquid holdup in foam.
Characterization and validation protocols for quantifying liquid content in a protein foam by gamma-scintigraphy were developed. Spatial resolution, count resolution and volume resolution values were measured to determine the analytical limitations of the apparatus. Scintigraphic measures of volume, in both liquid and dispersed media, correlated well with physical measures. Ionic interaction between [99mTc]pertechnetate and bovine serum albumin was undetectable by gel permeation. These results confirm that gamma-scintigraphy can be used to quantify liquid holdup in protein foams of pharmaceutical interest.
Journal Article↗
Histidine tagged protein recovery from tobacco extract by foam fractionation.
Tobacco plants have the potential to be used for the production of proteins for pharmaceutical applications. This work describes a novel protein recovery strategy where the protein of interest is "tagged" with a histidine sequence, which forms a complex with cobalt ions and surfactant possessing a chelating functionality, such that the protein is recovered in the foamate of a foam fractionation step. His-gus, a histidine-tagged enzyme, was chosen as a model protein to study the feasibility of this strategy. The His-gus is recovered from spiked prefoamed tobacco extract by foam fractionation in the presence of surfactant and cobalt ions with an enrichment of 1.29 and a recovery of 21.5% in terms of an adjusted activity.
Chemical Fractionation↗