Nonuniform Drug Research Articles

HPMC Extended-Release Multi-Composite Matrix for Co-delivery of Oxcarbamazepine and Vitamin D.

Background: Carbamazepine (CBZ) is considered as first-line treatment for epilepsy. The literature has signified a history of non-uniform drug performance and clinical failures. However, many studies suggested that Oxcarbazepine (OXC), a structural analog of CBZ, may have an equivalent antiepileptic effect. OXC follows a different metabolic pathway other than CBZ. However, both share the same mechanism of action by blocking voltage-gated sodium channels. Objectives: This study aimed to form hydroxypropyl methylcellulose (HPMC) extended-release tablets containing OXC combined with vitamin D. Methods: These formulated tablets were tested for their dissolution rate, tablet hardness, friability, thickness and pharmacokinetic parameters (Cmax and Cmin). Blood sodium levels were additionally investigated to ensure the absence of hyponatremia; the main side effect of long-term use of CBZ and some of its derivatives. Results: The use of HPMC inhibited the formation of dihydrate OXC form thus offering a significant extended-release profile. OXC also showed a highlighted capability to attain high bioavailability. Microcrystalline cellulose (MCC) was also added to tablets formed to inhibit polymorphic transformation. Tablets containing OXC co-delivered with vitamin D ensured significantly decreased susceptibility to hyponatremia, and an extended-release profile was evident. Lower amounts of OXC were loaded in formed tablets containing vitamin D owing to the synergistic effect between vitamin D and antiepileptic drugs. Conclusion: Conclusively, employing these newly HPMC-constructed tablets of OXC co-delivered with vitamin D appeared to be a promising option for the effective management of epilepsy with least side effects.

Transport cocktails for cancer therapeutics

Beyond biological cell heterogeneity, evidenced by different resistances to therapeutics, “delivery heterogeneity” crucially limits treatment efficacy for advanced solid tumors: variations in therapeutic drug delivery to different tumor areas (perivascular, perinecrotic) leading to nonuniform drug concentrations/doses and to unsuccessful treatment (cancer cell kill). Short-range (40–80 µm), high energy (1–5 MeV) α particles successfully address the biological heterogeneity: the double-strand DNA breaks they cause make them impervious to cell resistance mechanisms. Multiresponsive nanocarriers and/or engineered antibody-drug-conjugates are elegant approaches to delivering such α-particle emitters. Delivery heterogeneity, however, remains a challenge in established (i.e., large, vascularized) tumors. Remarkably, delivery properties enabling efficacy at the cell scale (targeting selectivity, affinity, cell drug uptake) may act against spatial delivery uniformity at the tumor scale (binding-site barrier effect). We have previously demonstrated, in different mouse models, that spatial delivery uniformity, key to the effective killing of solid tumors, can be achieved utilizing combinations of different, distinct delivery carriers of the same emitter, but with different, complementary delivery properties, “leaving no cancer cell behind.” We build first principles reaction-transport models (quantitatively informed by experiments) that explain the “geographically complementary” behaviors of such carrier cocktails, and help optimally design these cocktails and their delivery protocols. Published by the American Physical Society 2024

Dried blood spot sampling coupled with liquid chromatography-tandem mass for simultaneous quantitative analysis of multiple cardiovascular drugs

Dried Blood Spots (DBS) revolutionize therapeutic drug monitoring using LC-MS for the precise quantification of cardiovascular drugs (CDs), enabling personalized treatment adapted to patient-specific pharmacokinetics with minimal invasiveness. This study aims to achieve simultaneous quantification of eight CDs in DBS, overcoming physicochemical challenges. A two-step protein precipitation method was used for simple and precise sample preparation. The drugs were analyzed using LC-MS/MS in ESI positive-ion mode, showing high sensitivity and linearity, with a correlation coefficient (r2) exceeding 0.999, after being separated on a reversed-phase chromatography by gradient elution of DW-acetonitrile containing 0.1 % formic acid + 2 mM ammonium formate. The validation results indicate good selectivity, with no observed matrix effect and carry-over. The intra- and inter-day accuracy and precision were within 6 % for most drugs, except for digoxin and deslanoside at low therapeutic levels where the variation was within 20 %. Stability tests confirmed suitable DBS handling and storage conditions, indicating drug stability for at least 30 days at room temperature. The analysis of whole spot has demonstrated remarkable precision and reliability in all target drugs. The analysis of 3 mm internal diameter discs, punched in and out of DBS, presumed to contain 3 µL of blood, showed acceptable accuracy for most drugs, with less polar drugs like digoxin and deslanoside showing lower accuracy, indicating a need for further correction due to non-uniform drug distribution. Consequently, the developed LC-MS/MS method enables the quantification of multiple CDs in a single DBS analysis, while suggesting the potential for accuracy-based analysis.

Mechanistic Computational Modeling of Implantable, Bioresorbable Drug Release Systems.

Implantable, bioresorbable drug delivery systems offer an alternative to current drug administration techniques; allowing for patient-tailored drug dosage, while also increasing patient compliance. Mechanistic mathematical modeling allows for the acceleration of the design of the release systems, and for prediction of physical anomalies that are not intuitive and may otherwise elude discovery. This study investigates short-term drug release as a function of water-mediated polymer phase inversion into a solid depot within hours to days, as well as long-term hydrolysis-mediated degradation and erosion of the implant over the next few weeks. Finite difference methods are used to model spatial and temporal changes in polymer phase inversion, solidification, and hydrolysis. Modeling reveals the impact of non-uniform drug distribution, production and transport of H+ ions, and localized polymer degradation on the diffusion of water, drug, and hydrolyzed polymer byproducts. Compared to experimental data, the computational model accurately predicts the drug release during the solidification of implants over days and drug release profiles over weeks from microspheres and implants. This work offers new insight into the impact of various parameters on drug release profiles, and is a new tool to accelerate the design process for release systems to meet a patient specific clinical need.

Modeling Dual Drug Delivery from Eluting Stents: The Influence of Non-Linear Binding Competition and Non-Uniform Drug Loading.

There is increasing interest in simultaneous endovascular delivery of more than one drug from a drug-loaded stent into a diseased artery. There may be an opportunity to obtain a therapeutically desirable uptake profile of the two drugs over time by appropriate design of the initial drug distribution in the stent. Due to the non-linear, coupled nature of diffusion and reversible specific/non-specific binding of both drugs as well as competition between the drugs for a fixed binding site density, a comprehensive numerical investigation of this problem is critically needed. This paper presents numerical computation of dual drug delivery in a stent-artery system, accounting for diffusion as well as specific and non-specific reversible binding. The governing differential equations are discretized in space, followed by integration over time using a stiff numerical solver. Three different cases of initial dual drug distribution are considered. For the particular case of sirolimus and paclitaxel, results show that competition for a limited non-specific binding site density and the significant difference in the forward/backward reaction coefficients play a key role in determining the nature of drug uptake. The nature of initial distribution of the two drugs in the stent is also found to influence the binding process, which can potentially be used to engineer a desirable dual drug uptake profile. These results help improve the fundamental understanding of endovascular dual drug delivery. In addition, the numerical technique and results presented here may be helpful for designing and optimizing other drug delivery problems as well.

Treatment of Hypertrophic Scars with Corticoid-Embedded Dissolving Microneedles.

Hypertrophic scarring (HTS) is frequently observed after deep dermal and full-thickness skin defects. Local drug delivery in HTS has been shown more effective compared to other (minimally) invasive treatments. Disadvantages being operator-dependency and non-uniform drug distribution. Moreover, injections are painful and difficult when confronted with extensive scars or HTS in children. Corticoid-embedded dissolving microneedles (CEDMN) were developed that provide painless skin penetration and direct dermal drug delivery. Hyaluronic acid-based DMN and CEDMN patches were utilized. Structural analysis was performed via nuclear magnetic resonance (NMR) spectroscopy while gel permeation chromatography (GPC) was applied to determine chain length (molar mass) and dispersity of hyaluronic acid. Mechanical properties were evaluated by compression testing. Five burn victims with HTS were included. For each individual, three comparable scars were chosen. One control scar was left untreated. Two scars were treated with either 600 or 800 µm CEDMN patches. Patients were treated monthly for 4 months. Treatment with 800 µm CEDMN was initiated after 8 weeks. Assessor-blinded POSAS was registered. Hydration, evaporation, color and elasticity were recorded. The physico-chemical characterization suggests that the mechanical properties enable skin penetration and adequate drug delivery. Patients experienced the therapy as painless. According to the POSAS, all scars improved over time. However, the scars that were treated with CEDMN patches improved faster and with increased increment. The 800 µm CEDMN ensured the fastest POSAS-decrease. Hyaluronic acid-based CEDMN patches are valuable alternatives to intracicatrical injections, as they offer a painless and effective method for administering corticosteroids in HTS.

Modeling and Analysis of Nanoparticle with Non-Uniform Drug Concentration Distribution: How to Approach a Programmed Delivery?

Modeling and Analysis of Nanoparticle with Non-Uniform Drug Concentration Distribution: How to Approach a Programmed Delivery?

Effect of Manufacturing Process on the Retention of Abuse-Deterrent Properties of PEO-Matrix Tablets.

Polyethylene oxide (PEO) is a widely used polymer in the development of abuse-deterrent oral formulations. Different manufacturing processes including direct compression (DC) followed by sintering, wet granulation (WG) followed by compression and sintering, and hot melt extrusion (HME) can be used to manufacture abuse-deterrent oral drug products. Three different manufacturing processes (DC, WG, HME) were evaluated to test the retention of their abuse-deterrent features following attempts to grind the tablets or extrudates. In vitro drug release studies were conducted on 10% and 32% drug-loaded tablets/extrudates prepared using these manufacturing methods, and the release profiles from all formulations showed good extended-release properties. Drug content analysis on the granules obtained from tablets prepared by direct compression showed non-uniform drug distribution where an unexpectedly high drug content was present in the smallest size (< 250µm) granules, sizes which are likely to be inhaled by abusers. Granules from tablets prepared by wet granulation showed improved drug distribution across all granule sizes formed after grinding. Drug content testing on the granules obtained from extrudates prepared using hot melt extrusion showed excellent drug content uniformity along with sufficient strength to resist grinding into smaller particles. The retention of the abuse-deterrent properties of a dosage form following attempts to extract or abuse the drug is an important product characteristic, and the product design, formulation components, and manufacturing processes can all play critical roles in the retention of the desired abuse-deterrent properties.

A Two-Photon Microimaging-Microdevice System for Four-Dimensional Imaging of Local Drug Delivery in Tissues.

Advances in the intratumor measurement of drug responses have included a pioneering biomedical microdevice for high throughput drug screening in vivo, which was further advanced by integrating a graded-index lens based two-dimensional fluorescence micro-endoscope to monitor tissue responses in situ across time. While the previous system provided a bulk measurement of both drug delivery and tissue response from a given region of the tumor, it was incapable of visualizing drug distribution and tissue responses in a three-dimensional (3D) way, thus missing the critical relationship between drug concentration and effect. Here we demonstrate a next-generation system that couples multiplexed intratumor drug release with continuous 3D spatial imaging of the tumor microenvironment via the integration of a miniaturized two-photon micro-endoscope. This enables optical sectioning within the live tissue microenvironment to effectively profile the entire tumor region adjacent to the microdevice across time. Using this novel microimaging-microdevice (MI-MD) system, we successfully demonstrated the four-dimensional imaging (3 spatial dimensions plus time) of local drug delivery in tissue phantom and tumors. Future studies include the use of the MI-MD system for monitoring of localized intra-tissue drug release and concurrent measurement of tissue responses in live organisms, with applications to study drug resistance due to nonuniform drug distribution in tumors, or immune cell responses to anti-cancer agents.

Triplex PCR combined with magnetic separation strategy for rapid and specific detection of methicillin-resistant Staphylococcus aureus in hospital samples

Due to the massive use of antibiotics, clinical highly pathogenic bacteria methicillin-resistant Staphylococcus aureus (MRSA) have emerged. Given its non-uniform drug resistance, it brings numerous difficulties for clinical diagnostic tests. This study aimed to establish a fast and accurate method to detect MRSA in hospital samples. In order to shorten the detection time and eliminate the influence of matrix on the detection results, so as to improve the detection sensitivity. In this study, magnetic separation (MS) technology was used for pre-treatment of samples, and triplex PCR was established using mecA, nuc and flic genes to realize the detection of MRSA. The results showed that the lowest detection limit of MRSA in blood samples and cerebrospinal fluid could reach 102 CFU/mL and 103 CFU/mL. Therefore, the MS technology combined with triplex PCR assay established in this study is expected to provide a strong basis for the detection of MRSA in hospital samples.

The effect of wet spinning conditions on the structure and properties of poly-4-hydroxybutyrate fibers.

Polyhydroxyalkanoates (PHAs), also known as bacterial polyesters, are considered novel polymers for fabricating biomedical products, such as sutures and hernia meshes, because of their biocompatibility and slow biodegradability. Poly-4-hydroxybutyrate (P4HB) is a commonly used PHA that was explored in this study as an absorbable biomaterial for several medical applications, including controlled drug delivery. Currently, P4HB is melt spun and drawn into filaments at high processing temperatures (~200°C), precluding the incorporation of thermally sensitive drugs within the polymer during melt spinning. Post-spinning drug incorporation can potentially cause nonuniform drug absorption that leads to an uneven release profile. This raises the need for a low temperature spinning process for these polymers. Until now, there has been no defined procedure to produce P4HB fibers through a low temperature solution spinning process. This study focuses on determining suitable wet spinning conditions to form continuous P4HB fibers. After several preliminary tests, it was found that a chloroform-based spin dope with 10-15% polymer concentration facilitated the extrusion of continuous stretchable fibers into a coagulation bath containing reagent alcohol. Subsequently, several P4HB fibers were spun with various spin dope concentrations, coagulation bath temperatures, and spin draw ratios to assess their effect on fiber structure and properties.

Abstract PO-058: Intratumoral distribution and retention of gold nanoparticles characterized by computed tomography in a non-small cell lung cancer model

Abstract Lung cancer produces the highest number of cancer-related deaths worldwide. Currently, Non-Small Cell Lung Cancer (NSCLC) accounts for more than 85% of those cases. To date, achieving an early and precise diagnosis of NSCLC remains challenging due to extensive intratumor heterogeneity, which concerns not only to tumor epithelial cells but also the diverse microenvironment with which the tumor cells interact. In addition, genetic and phenotypic tumor heterogeneity and consequent non-uniform spatial drug distribution can lead to therapy resistance in cancer treatment. Therefore, visualization of the tumor microenvironment using morphological imaging techniques such as computed tomography (CT) can better clarify structure, vasculature, and biodistribution, making possible optimization of applications in the fields of diagnostics as well as individualized treatment. In this study, we aim to evaluate the intratumoral distribution of Gold Nanoparticles (GNPs) in Lewis Lung Carcinoma (LLC) tumor-bearing mice using high resolution CT preclinical imaging. We hypothesize that by exploiting the adsorption of molecules on the GNP surface, we can influence the intratumoral distribution and retention of the particles. In fact, GNPs exhibit high X-Ray attenuation and optimal biocompatibility, compared to the common side effects associated with the administration of standard contrast agents. GNPs approximately 34 nm in diameter are synthesized and surface passivated with Bovine Serum Albumin (BSA) to reduce opsonization and improve colloidal stability. CT phantom imaging is used to determine X-ray attenuation as a function of GNP concentration and surface functionalization. Particle uptake in vitro within the LLC cells was dependent on surface passivation. An in vivo study is performed by injecting intratumorally, concentrated GNPs into LLC-solid tumors grown on the right flank of 6-week old female C57BL/6 mice. Ten days post-injection, follow-up assessments with CT imaging and quantifications show the intratumoral distribution and retention of the particles. In vivo results show significant heterogeneity in the intratumoral biodistribution of GNPs dependent on surface passivation. BSA-GNPs perfuse predominately along the tumor periphery, allowing the visualization of the tumor boundaries, with few depositions throughout the entire tumor volume over time. This response suggests perfusion rather than permeability as the limiting factor for tumor accumulation of the GNPs. Citation Format: Rossana Terracciano, Sara Ricchetti, E. Brian Butler, Danilo Demarchi, Alessandro Grattoni, Carly S. Filgueira. Intratumoral distribution and retention of gold nanoparticles characterized by computed tomography in a non-small cell lung cancer model [abstract]. In: Proceedings of the AACR Virtual Special Conference on Tumor Heterogeneity: From Single Cells to Clinical Impact; 2020 Sep 17-18. Philadelphia (PA): AACR; Cancer Res 2020;80(21 Suppl):Abstract nr PO-058.

Precisely Assembled Nanoparticles against Cisplatin Resistance via Cancer-Specific Targeting of Mitochondria and Imaging-Guided Chemo-Photothermal Therapy.

Cisplatin resistance in tumor cells is known mainly due to the reduced accumulation of platinum ions by efflux, detoxification by intracellular GSH, and nucleotide excision repair machinery-mediated nuclear DNA repair. In this work, theranostic Pt(IV)-NPs, which are precisely self-assembled by biotin-labeled Pt(IV) prodrug derivative and cyclodextrin-functionalized IR780 in a 1:1 molecular ratio, have been developed for addressing all these hurdles via mitochondria-targeted chemotherapy solely or chemophotothermal therapy. In these nanoparticles, IR780 as a small-molecule dye acts as a mitochondria-targeting ligand to make Pt(IV)-NPs relocate finally in the mitochondria and release cisplatin. As demonstrated by in vitro and in vivo experiments, Pt(IV)-NPs can markedly facilitate cancer-specific mitochondrial targeting, inducing mitochondrial dysfunction and mitochondrial DNA (mtDNA) damage, thus greatly increasing the Pt accumulation, reducing the GSH levels, and avoiding DNA repair machinery in cisplatin-resistant cancer cells (A549R), finally resulting in significant inhibition of A549R tumor growth on animal models by chemotherapy solely. Upon near-infrared irradiation, mitochondria-targeted chemophotothermal synergistic therapy can be realized, further overcoming cisplatin resistance and even eliminating A549R tumors completely. Moreover, such novel Pt(IV)-NPs integrate multimodal targeting (cancer and mitochondria targeting), imaging (near-infrared imaging and photoacoustic imaging), and therapeutic (chemo- and photothermal therapy) moieties in a constant ratio (1:1:1) into a single, reproducible, and structurally homogeneous entity, avoiding nonuniform drug loading and premature leakage as well as the discrete steps of imaging and therapy, which thus is more beneficial for precise therapeutics and future clinical translation.

Non-uniform drug distribution matrix system (NUDDMat) for zero-order release of drugs with different solubility.

A decrease in the drug release rate over time typically affects the performance of hydrophilic matrices for oral prolonged release. To address such an issue, a Non-Uniform Drug Distribution Matrix (NUDDMat) based on hypromellose was proposed and demonstrated to yield zero-order release. The system consisted of 5 overlaid layers, applied by powder layering, having drug concentration decreasing from the inside towards the outside of the matrix according to a descending staircase function. In the present study, manufacturing and performance of the described delivery platform were evaluated using drug tracers having different water solubility. Lansoprazole, acetaminophen and losartan potassium were selected as slightly (SST), moderately (MST) and highly (HST) soluble tracers. By halving the thickness of the external layer, which contained no drug, linear release of HST and MST was obtained. The release behavior of the NUDDMat system loaded with a drug having pH-independent solubility was shown to be consistent in pH 1.2, 4.5 and 6.8 media. Based on these results, feasibility of the NUDDMat platform by powder layering was demonstrated using drugs having different physico-technological characteristics. Moreover, its ability to generate zero-order release was proved in the case of drugs with water solubility in a relatively wide range.

Spatial heterogeneity of nanomedicine investigated by multiscale imaging of the drug, the nanoparticle and the tumour environment.

Genetic and phenotypic tumour heterogeneity is an important cause of therapy resistance. Moreover, non-uniform spatial drug distribution in cancer treatment may cause pseudo-resistance, meaning that a treatment is ineffective because the drug does not reach its target at sufficient concentrations. Together with tumour heterogeneity, non-uniform drug distribution causes “therapy heterogeneity”: a spatially heterogeneous treatment effect. Spatial heterogeneity in drug distribution occurs on all scales ranging from interpatient differences to intratumour differences on tissue or cellular scale. Nanomedicine aims to improve the balance between efficacy and safety of drugs by targeting drug-loaded nanoparticles specifically to tumours. Spatial heterogeneity in nanoparticle and payload distribution could be an important factor that limits their efficacy in patients. Therefore, imaging spatial nanoparticle distribution and imaging the tumour environment giving rise to this distribution could help understand (lack of) clinical success of nanomedicine. Imaging the nanoparticle, drug and tumour environment can lead to improvements of new nanotherapies, increase understanding of underlying mechanisms of heterogeneous distribution, facilitate patient selection for nanotherapies and help assess the effect of treatments that aim to reduce heterogeneity in nanoparticle distribution.In this review, we discuss three groups of imaging modalities applied in nanomedicine research: non-invasive clinical imaging methods (nuclear imaging, MRI, CT, ultrasound), optical imaging and mass spectrometry imaging. Because each imaging modality provides information at a different scale and has its own strengths and weaknesses, choosing wisely and combining modalities will lead to a wealth of information that will help bring nanomedicine forward.

Modeling three-dimensional invasive solid tumor growth in heterogeneous microenvironment under chemotherapy.

A systematic understanding of the evolution and growth dynamics of invasive solid tumors in response to different chemotherapy strategies is crucial for the development of individually optimized oncotherapy. Here, we develop a hybrid three-dimensional (3D) computational model that integrates pharmacokinetic model, continuum diffusion-reaction model and discrete cell automaton model to investigate 3D invasive solid tumor growth in heterogeneous microenvironment under chemotherapy. Specifically, we consider the effects of heterogeneous environment on drug diffusion, tumor growth, invasion and the drug-tumor interaction on individual cell level. We employ the hybrid model to investigate the evolution and growth dynamics of avascular invasive solid tumors under different chemotherapy strategies. Our simulations indicate that constant dosing is generally more effective in suppressing primary tumor growth than periodic dosing, due to the resulting continuous high drug concentration. In highly heterogeneous microenvironment, the malignancy of the tumor is significantly enhanced, leading to inefficiency of chemotherapies. The effects of geometrically-confined microenvironment and non-uniform drug dosing are also investigated. Our computational model, when supplemented with sufficient clinical data, could eventually lead to the development of efficient in silico tools for prognosis and treatment strategy optimization.

Novel hydrophilic matrix system with non-uniform drug distribution for zero-order release kinetics

A decrease in the release rate over time is typically encountered when dealing with hydrophilic matrix systems for oral prolonged release due to progressive increase of the distance the drug molecules have to cover to diffuse outwards and reduction of the area of the glassy matrix at the swelling front. In order to solve this issue, a novel formulation approach based on non-uniform distribution of the active ingredient throughout the swellable polymer matrix was proposed and evaluated. Various physical mixtures of polymer (high-viscosity hypromellose) and drug tracer (acetaminophen), having decreasing concentrations of the latter, were applied by powder-layering onto inert core seeds. The resulting gradient matrices showed to possess satisfactory physico-technological characteristics, with spherical shape and consistent thickness of the layers sequentially applied. The non-uniform matrix composition pursued was confirmed by Raman mapping analysis. As compared with a system having uniform distribution of the drug tracer, the multi-layer formulations were proved to enhance linearity of release. The simple design concept, advantageous technique, which involves no solvents nor high-impact drying operations, and the polymeric material of established use make the delivery platform hereby proposed a valuable strategy to improve the performance of hydrophilic matrix systems.

Nanoparticle Optimization for Enhanced Targeted Anticancer Drug Delivery.

Nanoparticle (NP)-based drug delivery is a promising method to increase the therapeutic index of anticancer agents with low median toxic dose. The delivery efficiency, corresponding to the fraction of the injected NPs that adhere to the tumor site, depends on NP size a and aspect ratio AR. Values for these variables are currently chosen empirically, which may not result in optimal targeted drug delivery. This study applies rigorous optimization to the design of NPs. A preliminary investigation revealed that delivery efficiency increases monotonically with a and AR. However, maximizing a and AR results in nonuniform drug distribution, which impairs tumor regression. Therefore, a multiobjective optimization (MO) problem is formulated to quantify the trade-off between NPs accumulation and distribution. The MO is solved using the derivative-free mesh adaptive direct search algorithm. Theoretically, the Pareto-optimal set consists of an infinite number of mathematically equivalent solutions to the MO problem. However, interesting design solutions can be identified subjectively, e.g., the ellipsoid with a major axis of 720 nm and an aspect ratio of 7.45, as the solution closest to the utopia point. The MO problem formulation is then extended to optimize NP biochemical properties: ligand-receptor binding affinity and ligand density. Optimizing physical and chemical properties simultaneously results in optimal designs with reduced NP sizes and thus enhanced cellular uptake. The presented study provides an insight into NP structures that have potential for producing desirable drug delivery.

Abstract 12072: Damage to Coating Polymer Can Cause Serious Complications After Drug-Eluting Stent Implantation: A Pathological Study in Human Coronary Arteries

Introduction: Polymer coating is indispensable to optimize controlled drug release kinetics following drug-eluting stent (DES) implantation. However, how it can be damaged during the stenting procedure and the subsequent clinico-pathological events are not well studied. Hypothesis: We histopathologically assessed the hypothesis that damage to polymer coating can hinder DES efficacy. Methods: The study sample comprised 32 DES-implanted lesions obtained by autopsy from 2.5 to 49 months after stenting: 27 with durable polymers (Cypher, 12; Taxus, 6; Endeavor, 4; and Xience, 5) and 5 with biodegradable polymers coated only on the abluminal surface (Nobori, 3 and Ultimaster, 2). Tortuous lesions accounted for 60% and calcified lesions for 88%. We examined microscopically at least six slices from each lesion. Results: Polymer cracking or delamination was observed in about 6% of Cypher struts and 4% of Taxus struts. In two Cypher-implanted lesions with stent thrombosis occurring beyond one year after stent implantation, significant detachment of polymer fragments phagocytosed by giant cells was observed, and their arterial walls were aneurysmally dilated with extensive inflammatory infiltration of the intima, media, and adventitia, predominantly consisting of T cells, eosinophils, and considerable giant cells. In Xience-implanted lesions, polymer damage was little. In contrast, in most Endeavor-implanted lesions, large spallings of the polymer were found, and numerous phagocytosed polymer remnants scattered in the thickened neointima. In Nobori- or Ultimaster-implanted calcified lesions within 4 months after the procedure, remarkable detachment of polymer coating resulted in severe inflammatory reaction consisting of macrophages and lymphocytes. Conclusions: Polymer disruption may result in nonuniform drug distribution that may allow neointimal hyperplasia in the DES-implanted lesions. Moreover, polymer cracking may induce adverse and interrelated effects such as local inflammation and amplified cellular response, followed by very late stent thrombosis. Compared with polymer around the stent struts, delamination of abluminal polymer might occurr more easily when it is delivered through a calcified coronary artery.

Zero-Order Antibiotic Release from Multilayer Contact Lenses: Nonuniform Drug and Diffusivity Distributions Produce Constant-Rate Drug Delivery.

A novel approach to zero-order constant-rate drug delivery from contact lenses is presented. Quasi-Case II non-Fickian transport is achieved by nonuniform drug and diffusivity distributions within three-layer bimodal amphiphilic conetworks (β-APCNs). The center layer is a highly oxygen permeable β-APCN matrix, which contains the drug and exhibits a high drug diffusivity. The outer β-APCN layers contain no-drug and are loaded with vitamin E, which slows diffusion. In contrast to single-layer neat-polymer and vitamin E-loaded films that display first-order "burst" kinetics, it is demonstrated experimentally and by modeling that the combined effect of nonuniform distribution of drug loading and diffusion constants within the three-layer lens maintains low local drug concentration at the lens-fluid interface and yields zero-order drug delivery. The release rates of topical antibiotics provide constant-rate therapeutic-level delivery with appropriate oxygen permeability for at least 30 h, at which time ≈25% of the drug was released.