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1.
Anal Bioanal Chem ; 411(12): 2707-2714, 2019 May.
Article in English | MEDLINE | ID: mdl-30888469

ABSTRACT

The Jatropha curcas plant (Jatropha) has been proposed as a source of biodiesel fuel, as it yields crude glycerol as an abundant by-product. Its by-products could serve as a starting material in making glycerol for FDA-regulated products. Jatropha is not regarded as a source of edible vegetable oil since it contains phorbol esters (PEs). PEs, even at very low exposure concentrations, demonstrate various toxicities in humans and animals, but may not be detected by routine impurity analyses. Here, we demonstrate the development of a rapid and simplified method for the detection and quantification of Jatropha-derived PE toxins using ambient ionization mass spectrometry. To do this, we successfully coupled a paper spray ambient ionization source with an ion trap portable mass spectrometer. The paper spray source was assembled using chromatography papers, and analyte ions were generated by applying a high voltage to a wetted paper triangle loaded with PE standards. For method development, we used commercially available PE standards on an ion trap portable mass spectrometer. Standard solutions were prepared using ethanol with PE concentrations ranging from 1.0 to 0.0001 mg mL-1. Spike and recovery experiments were performed using USP grade and commercially available glycerol. To discern chemical differences between samples, we applied multivariate data analysis. Based on the results obtained, paper spray coupled with a portable mass spectrometric method can be successfully adopted for the analysis of toxic contaminants present in glycerol-based consumer products with LOD and LOQ of 0.175 µg mL-1 and 0.3 µg mL-1 respectively. This direct, simple design, and low-cost sampling and ionization method enables fast screening with high sensitivity in non-laboratory settings.


Subject(s)
Drug Contamination , Fluorescent Dyes/chemistry , Glycerol/chemistry , Mass Spectrometry/methods , Paper , Phorbol Esters/analysis , Animals , Biocompatible Materials , Ferric Compounds/chemistry , Flowers/chemistry , Humans , Jatropha/chemistry , Jatropha/embryology , Limit of Detection , Microscopy, Electron, Transmission , Seeds/chemistry , Spectrophotometry, Ultraviolet , Spectrum Analysis/methods
2.
Pharm Dev Technol ; 22(1): 35-44, 2017 Feb.
Article in English | MEDLINE | ID: mdl-26895348

ABSTRACT

Potential connections between release profiles and solvent evaporation rates alongside polymer chemistry were elucidated for the release of tetracycline hydrochloride from two different poly (d, l-lactide-co-glycolide) (PLGA) film matrices containing high drug fractions (50%, 30%, and 15%), and prepared at two distinct solvent evaporation rates. At highest tetracycline concentrations (50%), (i) the early release rates were ≤0.5 µg/min in all cases; (ii) release was linear from systems fabricated with lower lactic content and slower solvent evaporation rate and bimodal from systems fabricated with higher lactic content and faster evaporation rate; (iii) surface fractions covered by the drug were similar at both evaporation rates for 85:15 PLGA but very different for 50:50 PLGA, leading to unexpectedly reduced early release from 50:50 PLGA than from 85:15 PLGA when both the matrices were fabricated using a slower evaporation rate. These features remained unaffected in case of low drug concentration. Results suggested that during the formation of the drug-polymer microstructure, the combined effect of polymer chemistry and solvent evaporation rate sets apart the surface characteristics and the initial release profiles of systems containing high drug fraction, and an appropriate combination of these parameters may be utilized to control the early stage of drug release.


Subject(s)
Anti-Bacterial Agents/administration & dosage , Delayed-Action Preparations/chemistry , Drug Liberation , Lactic Acid/chemistry , Polyglycolic Acid/chemistry , Tetracycline/administration & dosage , Anti-Bacterial Agents/chemistry , Polylactic Acid-Polyglycolic Acid Copolymer , Solubility , Solvents/chemistry , Tetracycline/chemistry , Volatilization
3.
AAPS PharmSciTech ; 16(4): 811-23, 2015 Aug.
Article in English | MEDLINE | ID: mdl-25563817

ABSTRACT

The drug coating process for coated drug-eluting stents (DES) has been identified as a key source of inter- and intra-batch variability in drug elution rates. Quality-by-design (QbD) principles were applied to gain an understanding of the ultrasonic spray coating process of DES. Statistically based design of experiments (DOE) were used to understand the relationship between ultrasonic atomization spray coating parameters and dependent variables such as coating mass ratio, roughness, drug solid state composite microstructure, and elution kinetics. Defect-free DES coatings composed of 70% 85:15 poly(DL-lactide-co-glycolide) and 30% everolimus were fabricated with a constant coating mass. The drug elution profile was characterized by a mathematical model describing biphasic release kinetics. Model coefficients were analyzed as a DOE response. Changes in ultrasonic coating processing conditions resulted in substantial changes in roughness and elution kinetics. Based on the outcome from the DOE study, a design space was defined in terms of the critical coating process parameters resulting in optimum coating roughness and drug elution. This QbD methodology can be useful to enhance the quality of coated DES.


Subject(s)
Drug-Eluting Stents , Ultrasonics , Chromatography, High Pressure Liquid , Everolimus/chemistry , Everolimus/pharmacokinetics , Microscopy, Atomic Force , Microscopy, Electron, Scanning , Polyglactin 910 , Surface Properties
5.
J Biomech Eng ; 136(2): 021027, 2014 Feb.
Article in English | MEDLINE | ID: mdl-24317017

ABSTRACT

The objective of this study is to develop a theoretical model to simulate temperature fields in a joint simulator for various bearing conditions using finite element analyses. The frictional heat generation rate at the interface between a moving pin and a stationary base is modeled as a boundary heat source. Both the heat source and the pin are rotating on the base. We are able to conduct a theoretical study to show the feasibility of using the COMSOL software package to simulate heat transfer in a domain with moving components and a moving boundary source term. The finite element model for temperature changes agrees in general trends with experimental data. Heat conduction occurs primarily in the highly conductive base component, and high temperature elevation is confined to the vicinity of the interface in the pin. Thirty rotations of a polyethylene pin on a cobalt-chrome base for 60 s generate more than 2.26 °C in the temperature elevation from its initial temperature of 25 °C at the interface in a baseline model with a rotation frequency of 0.5 Hz. A higher heat generation rate is the direct result of a faster rotation frequency associated with intensity of exercise, and it results in doubling the temperature elevations when the frequency is increased by100%. Temperature elevations of more than 7.5 °C occur at the interface when the friction force is tripled from that in the baseline model. The theoretical modeling approach developed in this study can be used in the future to test different materials, different material compositions, and different heat generation rates at the interface under various body and environmental conditions.


Subject(s)
Computer-Aided Design , Energy Transfer , Equipment Failure Analysis/instrumentation , Equipment Failure Analysis/methods , Hip Prosthesis , Models, Theoretical , Temperature , Computer Simulation , Friction , Thermal Conductivity
6.
J Biomed Mater Res B Appl Biomater ; 101(7): 1191-9, 2013 Oct.
Article in English | MEDLINE | ID: mdl-23564439

ABSTRACT

Drug-polymer composite coatings, composed of styrene-isobutylene-styrene (SIBS) tri-block copolymers, are frequently used in controlled drug release biomedical device applications. In this work, we used atomic force microscopy to characterize the effects of different drug loadings and polymer chemistries (i.e., block copolymer ratio) on the variation of surface structures and compositions of SIBS-tetracycline (SIBS-TC) cast composites including tetracycline (TC) drug amount, drug phase size distribution, and drug and polymer phase morphologies. We tested the structural variations by fabricating and characterizing two types of composite specimens, that is, SIBS15 and SIBS30, composed of 15 and 30 Wt % of polystyrene (PS), respectively. The differences in the distribution of TC drug, PS, and polyisobutylene (PIB) polymer phase structures observed in SIBS15 and SIBS30 resulted in more drug at the surface of SIBS30 compared to SIBS15. To support the experimental findings, we have determined the Hildebrand solubility parameter of TC using molecular dynamics (MD) computation and compared it to the polymer components, PS and PIB. The MD results show that the solubility parameter of TC is much closer to that of PS than PIB, which demonstrates a higher thermodynamic stability of TC-PS mixtures.


Subject(s)
Anti-Bacterial Agents/chemistry , Drug Delivery Systems , Styrenes/chemistry , Tetracycline/chemistry
7.
J Pharm Sci ; 102(6): 1905-1914, 2013 Jun.
Article in English | MEDLINE | ID: mdl-23568279

ABSTRACT

Drug-eluting stent (DES) implantation is a common treatment for atherosclerosis. The safety and efficacy of these devices will depend on the uptake and distribution of drug into the vessel wall. It is established that the composition of atherosclerotic vessels can vary dramatically with patients' age and gender. However, studies focused on elucidating and quantifying the impact of these variations on important drug transport properties, such as diffusion (D) and partition (k) coefficients, are limited. We have developed an improved tissue mimic or artificial plaque to probe the effect of varying concentrations of plaque constituents on drug transport in vitro. Based on these artificial plaques, we have quantified the impact of gelatin (hydrolyzed collagen) and lipid (cholesterol) concentration on D and k using two model drugs, tetracycline and fluvastatin. We found that for tetracycline, increasing the collagen concentration from 0.025 to 0.100 (w/w) resulted in a fivefold decrease in diffusivity, whereas there was no discernible impact on solubility. Increasing the lipid concentration up to 0.034 (w/w) resulted in only minor changes to transport properties of tetracycline. However, fluvastatin exhibited nearly a fivefold increase in k and 10-fold decrease in D with increased lipid concentration. These results were in reasonable agreement with existing models and exhibited behavior consistent with previous observations on drugs commonly used in DES applications. These observations suggest that variations in the chemical characteristics of atherosclerotic plaque can significantly alter the release rate and distribution of drug following DES implantation.


Subject(s)
Anti-Bacterial Agents/metabolism , Anticholesteremic Agents/metabolism , Atherosclerosis/drug therapy , Fatty Acids, Monounsaturated/metabolism , Indoles/metabolism , Plaque, Atherosclerotic/chemistry , Tetracycline/metabolism , Atherosclerosis/metabolism , Atherosclerosis/pathology , Cholesterol/chemistry , Cholesterol/metabolism , Diffusion , Drug-Eluting Stents , Fluvastatin , Gelatin/chemistry , Gelatin/metabolism , Humans , Permeability , Plaque, Atherosclerotic/metabolism
8.
Med Devices (Auckl) ; 4: 1-10, 2011.
Article in English | MEDLINE | ID: mdl-22915924

ABSTRACT

Hyaluronic acid (HA), in linear or cross-linked form, is a common component of cosmetics, personal care products, combination medical products, and medical devices. In all cases, the ability of the HA solution or gel to wet surfaces and/or disrupt and lubricate interfaces is a limiting feature of its mechanism of action. We synthesized ferric ion-cross-linked networks of HA based on an adhesion barrier, varied the degree of cross-linking, and performed wetting goniometry, viscometry, and dynamic mechanical analysis. As cross-linking increases, so do contact angle, viscosity, storage modulus, and loss modulus; thus, wetting and lubrication are compromised. These findings have implications in medical device materials, such as adhesion barriers and mucosal drug delivery vehicles.

9.
J Biomed Mater Res B Appl Biomater ; 95(1): 9-18, 2010 Oct.
Article in English | MEDLINE | ID: mdl-20665680

ABSTRACT

Iron-crosslinked hyaluronic acid hydrogel (FeHA) has been used to reduce postsurgical adhesions in patients undergoing open, gynecological surgery. The performance of FeHA gel as an adhesion barrier device is influenced by many factors, including the physicochemical gel properties, which, in turn, depend on the chemistry and conditions of the device manufacturing. In this work, we demonstrate the effect of reaction pH on rheology and homogeneity of FeHA gels formulated in house and also compare the viscoelastic properties of FeHA gels with that of uncrosslinked HA solution of similar HA concentration and ionic strength. Dynamic mechanical analyses provide evidence that the reaction of HA with Fe(III) ions leads to the formation of "weak" gels. The viscoelastic properties and homogeneity of FeHA gels vary depending on the pH at which crosslinking was initiated. When solution pH, at the start of crosslinking, varied between 1.5 and 3, the low-shear rate viscosity of FeHA varied between 10,000 and 40,000 cPoise (10-40 Pa s). The highest steady-state shear viscosity and viscoelasticity were measured when pH was around 2.6, which is similar to the pH-dependent viscoelasticity of pure HA solution. Initiating HA crosslinking at pH ≤ 3 led to relatively homogenous solutions, while crosslinking higher pH > 3 caused instantaneous gel precipitation and inhomogeneities. Sensitivity of FeHA gel properties to small variations in reaction pH clearly supports the need for a tight manufacturing control during medical device fabrication.


Subject(s)
Gels/chemistry , Hyaluronic Acid/therapeutic use , Materials Testing/methods , Tissue Adhesions/prevention & control , Cross-Linking Reagents , Elasticity , Gels/therapeutic use , Hyaluronic Acid/chemistry , Hydrogen-Ion Concentration , Iron/chemistry , Postoperative Care/methods , Viscosity
10.
J Pharm Sci ; 99(6): 2777-85, 2010 Jun.
Article in English | MEDLINE | ID: mdl-20091828

ABSTRACT

A critical metrology issue for pharmaceutical industries is the application of analytical techniques for the characterization of drug delivery systems to address interrelationships between processing, structure, and drug release. In this study, cast coatings were formed from solutions of poly(styrene-b-isobutylene-b-styrene) (SIBS) and tetracycline in tetrahydrofuran (THF). These coatings were characterized by several imaging modalities, including time-of-flight secondary ion mass spectrometry (TOF-SIMS) for chemical imaging and analysis, atomic force microscopy (AFM) for determination of surface structure and morphology, and laser scanning confocal microscopy (LSCM), which was used to characterize the three-dimensional structure beneath the surface. The results showed phase separation between the drug and copolymer regions. The size of the tetracycline phase in the polymer matrix ranged from hundreds of nanometers to tens of microns, depending on coating composition. The mass of drug released was not found to be proportional to drug loading, because the size and spatial distribution of the drug phase varied with drug loading and solvent evaporation rate, which in turn affected the amount of drug released.


Subject(s)
Drug Delivery Systems , Pharmaceutical Preparations/analysis , Polymers/chemistry , Solvents/chemistry , Spectrometry, Mass, Secondary Ion/methods , Anti-Bacterial Agents , Dosage Forms , Microscopy, Atomic Force , Styrenes , Tetracycline
11.
J Biomed Mater Res B Appl Biomater ; 90(2): 688-99, 2009 Aug.
Article in English | MEDLINE | ID: mdl-19213052

ABSTRACT

To improve functionality and performance, controlled drug-release coatings comprised of drug and polymer are integrated with traditional medical devices, e.g., drug eluting stents. Depending on manufacturing conditions, these coatings can exhibit complex microstructures. Previously, a thermodynamically consistent model was developed for microstructure evolution in these systems to establish relationships between process variables, microstructure, and the subsequent release kinetics. Calculations based on the model were, in general, consistent with experimental findings. However, because of assumptions regarding the evaporation of solvent during fabrication, the model was unable to capture variations through the coating thickness that are observed experimentally. Here, a straightforward method is introduced to incorporate solvent evaporation explicitly into the model. Calculations are used to probe the impact of solvent evaporation rate and drug loading on the microstructure that forms during manufacturing and subsequent drug release kinetics. The predicted structures and release kinetics are found to be consistent with experimental observations. Further, the calculations demonstrate that solvent evaporation rate can be as critical to device performance as the amount of drug within the coating. For example, changes of a factor of five in the amount of drug released were observed by modifying the rate of solvent evaporation during manufacturing.


Subject(s)
Delayed-Action Preparations/pharmacology , Drug Delivery Systems , Solvents/chemistry , Anti-Bacterial Agents/administration & dosage , Chemistry, Pharmaceutical/methods , Coated Materials, Biocompatible , Computer Simulation , Drug Design , Kinetics , Microscopy, Confocal/methods , Models, Statistical , Reproducibility of Results , Tetracycline/administration & dosage , Thermodynamics
12.
J Pharm Sci ; 98(1): 169-86, 2009 Jan.
Article in English | MEDLINE | ID: mdl-18481310

ABSTRACT

In recent years, controlled release coatings, comprised of drug-polymer composites, have been integrated with medical devices, improving device functionality and performance. However, relationships between material properties, manufacturing environment, composite (micro)structure, and subsequent release kinetics are not well established. We apply a thermodynamically consistent model to probe the influence of drug-polymer chemistry (phobicity), drug loading, and evaporation rate on microstructure development during fabrication. For these structures, we compute release profiles for exposure to polymer-insoluble media and media in which the polymer readily dissolves. We find that with increasing drug-polymer phobicity, structural heterogeneities form at lower loadings and more rapid rates. The heterogeneities remain isolated and compact at low loadings and become interconnected as the drug to polymer ratio approaches 1.0. Release into polymer-insoluble media was dramatically enhanced by heterogeneities, resulting in up to a fourfold increase in drug release. In polymer-soluble media, however, heterogeneities diminished release. Although reductions of only 30% were typically observed, the absolute changes were much larger than observed in polymer-insoluble media. Our results suggest that improved comprehension and quantification of the physico-chemical properties in controlled release systems will enable the microstructure to be tailored to achieve desired responses that are insensitive to manufacturing variations.


Subject(s)
Delayed-Action Preparations/chemistry , Delayed-Action Preparations/pharmacokinetics , Models, Chemical , Pharmaceutical Preparations/chemistry , Kinetics , Pharmaceutical Preparations/metabolism , Polymers/chemistry , Polymers/pharmacokinetics , Surface Properties
13.
Acta Biomater ; 3(6): 851-64, 2007 Nov.
Article in English | MEDLINE | ID: mdl-17553761

ABSTRACT

A common method of controlling drug release has been to incorporate the drug into a polymer matrix, thereby creating a diffusion barrier that slows the rate of drug release. It has been demonstrated that the internal microstructure of these drug-polymer composites can significantly impact the drug release rate. However, the effect of processing conditions during manufacture on the composite structure and the subsequent effects on release behavior are not well understood. We have developed a diffuse-interface theory for microstructure evolution that is based on interactions between drug, polymer and solvent species, all of which may be present in either crystalline or amorphous states. Because the theory can be applied to almost any specific combination of material species and over a wide range of environmental conditions, it can be used to elucidate and quantify the relationships between processing, microstructure and release response in controlled drug release systems. Calculations based on the theory have now demonstrated that, for a characteristic delivery system, variations in microstructure arising due to changes in either drug loading or processing time, i.e. evaporation rate, could have a significant impact on both the bulk release kinetics and the uniformity of release across the system. In fact, we observed that changes in process time alone can induce differences in bulk release of almost a factor of two and typical non-uniformities of +/-30% during the initial periods of release. Because these substantial variations may have deleterious clinical ramifications, it is critical that both the system microstructure and the control of that microstructure are considered to ensure the device will be both safe and effective in clinical use.


Subject(s)
Drug Carriers/chemistry , Computer Simulation , Diffusion , Kinetics , Probability
14.
Anal Chem ; 74(9): 2133-8, 2002 May 01.
Article in English | MEDLINE | ID: mdl-12033317

ABSTRACT

A computer modeling technique has been developed which allows for the prediction of chromatographic separation and stationary-phase selectivity. This technique enables development of application-specific gas chromatographic columns by allowing for the simultaneous optimization of physical dimensions, flow and temperature programs, and stationary-phase composition. Stationary-phase selectivity is the most powerful tool available to achieve a separation; however most commercially available columns were not designed to have a selectivity specific to the separations for which they are used. The techniques described in this paper were developed to address this need.

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