Dinesh V. Patwardhan

Microstructure and Elution of Tetracycline from Block Copolymer Coatings

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.

Modeling microstructure development and release kinetics in controlled drug release coatings

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.

Ionically cross-linked hyaluronic acid: wetting, lubrication, and viscoelasticity of a modified adhesion barrier gel

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.

Impact of copolymer ratio on drug distribution in styrene-isobutylene-styrene block copolymers

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.

Antimicrobial and Anti-Biofilm Medical Devices: Public Health and Regulatory Science Challenges

This chapter introduces the public health challenge of medical device healthcare associated infections (MD-HAIs) and the regulatory science challenges involved with antimicrobial and anti-biofilm medical device technologies, including coatings and other modifications. In the United States, regulatory science is the science of developing new tools, standards, and approaches to assess the safety, efficacy, quality, and performance of all FDA-regulated products. Good regulatory science can facilitate consumer access to innovative medical products that are safe and effective. Section I looks at our increasing understanding of how colonization and biofilm may play a role in the pathogenesis of medical device associated infections as well as in the emergence of drug resistant microbes. Device colonization and biofilm have unique clinical features such as persistence that make them challenging to address. This challenge requires a coordinated response from medical device manufacturers, clinicians and public health/regulatory authorities. In Section II, we take a broad view beyond antimicrobial coatings to consider the range of possible medical therapies (e.g., device coatings, antimicrobials, vaccines) to prevent MD-HAIs, their use, limitations and safety. In Section III, we discuss regulatory definitions of the different types of technology and discuss mechanisms of action and the importance of understanding combination products. Then in Section IV, we focus specifically on the regulatory science of antimicrobial technologies for medical devices. We show how the paradigm shift from a planktonic model of microbial life to a biofilm model introduces significant challenges to the scientific assessment process.

Controlled initial surge despite high drug fraction and high solubility

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.

Theoretical Simulation of Temperature Elevations in a Joint Wear Simulator During Rotations

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.

Effect of Heparin Contaminated with Oversulfated Chondroitin Sulfate on the Collection and Analysis of Plasma~!2009-10-12~!2010-02-04~!2010-03-25~!

Oversulfated chrondroitin sulfate (OSCS) was recently identified as a contaminant of heparin and was associ- ated with serious adverse events in patients treated with heparin. Because heparin is a common component of blood col- lection tubes, we tested the effect of OSCS on the laboratory analysis of plasma. Blood from healthy volunteers (N=50) was collected into tubes containing various mixtures of heparin and OSCS. Samples were inspected for microclots and were analyzed for a panel of 28 routine laboratory tests. No microclots were observed in tubes that contained only heparin but were detected in 18%, 88% and 76% of plasma samples containing 5%, 15%, 20% OSCS (%weight relative to hepa- rin), respectively. OSCS at the highest dose (20%) caused a systematic bias for the following 6 tests: Lactate Dehydro- genase: 18% (12% to 24%); Triiodothyronine: -5.7% (-8.1% to -3.3%); Potassium: -2.8% (-4.2% to -1.4%); Total Protein: 2.5% (1.4% to 3.6%); Chloride: -1.4% (-1.8% to -1.0%) and Uric Acid: 1% (0.5% to 1.4%). In summary, OSCS contami- nation of heparin was found to potentially affect the anticoagulation of plasma and the analytical performance of several routine clinical laboratory tests.