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Release Mechanisms and Practical Percolation Threshold for Long-acting Biodegradable Implants: An Image to Simulation Study
Abstract
The development of long-acting drug formulations requires efficient characterization technique as the designed 6-12 months release duration renders real-time in vitro and in vivo experiments cost and time prohibitive. Using a novel image-based release modeling method, release profiles were predicted from X-Ray Microscopy (XRM) of T0 samples. A validation study with the in vitro release test shows good prediction accuracy of the initial burst release. Through fast T0 image-based release prediction, the impact of formulation and process parameters on burst release rate was investigated. Recognizing the limitations of XRM, correlative imaging with Focused Ion Beam Scanning Electron Microscopy (FIB-SEM) was introduced. A water stress test was designed to directly elucidate the formation of pores through polymer-drug-water interplay. Through an iterative correction method that considers poly(lactic-co-glycolic acid) (PLGA) polymer degradation, good agreement was achieved between release predictions using FIB-SEM images acquired from T0 samples and in vitro testing data. Furthermore, using image-based release simulations, a practical percolation threshold was identified that has profound influence on the implant performance. It is proposed as an important critical quality attribute for biodegradable long-acting delivery system, that needs to be investigated and quantified.
... Fig. 1c shows a representative image of a microsphere cross-section obtained using FIB-SEM, while Fig. 1d shows the AI assisted 3D reconstruction of hundreds of FIB-SEM images of the microspheres. Despite the powerful elucidation and quantification of intra-sphere microstructures, FIB-SEM is limited by its throughput as the technique requires several hours of imaging and analysis to determine the microstructure of one microsphere [12,13,15]. The time and cost required to determine the microstructure of a statistically representative number of microspheres would be prohibitive. ...
... molecular weight, L:G ratio, etc.) and drug properties were kept the same among the eight microsphere batches, thus ensuring that the only differences among the spheres would be due to the processing conditions of each sample. These processing condition changes will promote variations in the internal structure such as relative fractions of each phase, phase size and spatial distributions which have been shown to impact in vitro release performance [12,14,15,17]. XRM was utilized here to characterize the impact of these structural changes through AI-based analysis of the signal intensity of the microspheres. ...
The intra-sphere and inter-sphere structural attributes of controlled release microsphere drug products can greatly impact their release profile and clinical performance. In developing a robust and efficient method to characterize the structure of microsphere drug products, this paper proposes X-ray microscopy (XRM) combined with artificial intelligence (AI)-based image analytics. Eight minocycline loaded poly(lactic-co-glycolic acid) (PLGA) microsphere batches were produced with controlled variations in manufacturing parameters, leading to differences in their underlying microstructures and their final release performances. A representative number of microspheres samples from each batch were imaged using high resolution, non-invasive XRM. Reconstructed images and AI-assisted segmentation were used to determine the size distribution, XRM signal intensity, and intensity variation of thousands of microspheres per sample. The signal intensity within the eight batches was nearly constant over the range of microsphere diameters, indicating high structural similarity of spheres within the same batch. Observed differences in the variation of signal intensity between different batches suggests inter-batch non-uniformity arising from differences in the underlying microstructures associated with different manufacturing parameters. These intensity variations were correlated with the structures observed from higher resolution focused ion beam scanning electron microscopy (FIB-SEM) and the in vitro release performance for the batches. The potential for this method for rapid at-line and offline product quality assessment, quality control, and quality assurance is discussed.
... The goal is often to relate in vitro drug release data to in vivo performance. These models can further be improved with the use of high-resolution 3D imaging techniques to determine polymer microstructure, which can be used to correlate the kinetics of biodegradation to device microstructure, and also to the kinetics of drug release [180,181]. ...
Introduction
: Implantable devices can be designed to release drugs to localized regions of tissue at sustained and reliable rates. Advances in polymer engineering have led to the design and development of drug-loaded implants with predictable, desirable release profiles. Biodegradable polyesters exhibit chemical, physical, and biological properties suitable for developing implants for pain management, cancer therapy, contraception, antiviral therapy, and other applications.
Areas covered
: This article reviews the use of biodegradable polyesters for drug-loaded implants by discussing the properties of commonly used polymers, techniques for implant formulation and manufacturing, mechanisms of drug release, and clinical applications of implants as drug delivery devices.
Expert opinion
: Drug delivery implants are unique systems for safe and sustained drug release, providing high bioavailability and low toxicity. Depending on the implant design and tissue site of deployment, implants can offer either localized or systemic drug release. Due to the long history of use of degradable polyesters in medical devices, polyester-based implants represent an important class of controlled release technologies. Further, polyester-based implants are the largest category of drug delivery implants to reach the point of testing in humans or approval for human use.
... degradation, pore closure, swelling, etc.) which would represent a bottom-up approach. The construction of the polymer impact function is described in greater detail in a recent publication investigating the impact of drug network percolation on drug release [24]. ...
The distribution of the active pharmaceutical ingredient (API) within polymer-based controlled release drug products is a critical quality attribute (CQA). It is crucial for the development of such products, to be able to accurately characterize phase distributions in these products to evaluate performance and microstructure (Q3) equivalence. In this study, polymer, API, and porosity distributions in poly(lactic-co-glycolic acid) (PLGA) microspheres were characterized using a combination of focused ion beam scanning electron microscopy (FIB-SEM) and quantitative artificial intelligence (AI) image analytics. Through in-depth investigations of nine different microsphere formulations, microstructural CQAs were identified including the abundance, domain size, and distribution of the API, the polymer, and the microporosity. 3D models, digitally transformed from the FIB-SEM images, were reconstructed to predict controlled drug release numerically. Agreement between the in vitro release experiments and the predictions validated the image-based release modelling method. Sensitivity analysis revealed the dependence of release on the distribution and size of the API particles and the porosity within the polymeric microspheres, as captured through FIB-SEM imaging. To our knowledge, this is the first report showing that microstructural CQAs in PLGA microspheres derived from imaging can be quantitatively and predictively correlated with formulation and manufacturing parameters.
Ozurdex is an FDA-approved sustained-release, biodegradable implant formulated to deliver the corticosteroid dexamethasone to the posterior segment of the eye for up to 6 months. Hot-melt extrusion is used to prepare the 0.46 mm × 6 mm, rod-shaped implant by embedding the drug in a matrix of poly(lactic-co-glycolic acid) (PLGA) in a 60:40 drug:polymer ratio by weight. In our previous work, the Ozurdex implant was carefully studied and reverse engineered to produce a compositionally and structurally equivalent implant for further analysis. In this work, the reverse-engineered implant is thoroughly characterized throughout the in vitro dissolution process to elucidate the mechanisms of controlled drug release. The implant exhibits a triphasic release profile in 37 °C normal saline with a small burst release (1-2 %), a one-week lag phase with limited release (less than10 %), and a final phase where the remainder of the dose is released over 3-4 weeks. The limited intermolecular interaction between dexamethasone and PLGA renders the breakdown of the polymer the dominating mechanism of controlled release. A close relationship between drug release and total implant mass loss was observed. Unique chemical and structural differences were seen between the core of the implant and the implant surface driven by diffusional limitations, autocatalytic hydrolysis, and osmotic effects.
Introduction:
Ocular long-acting injectables and implants (LAIIs) deliver drug at a controlled release rate over weeks to years. A reduced dose frequency eases the treatment burden on patients, minimizes the potential for treatment-related adverse effects, and improves treatment adherence and persistence.
Areas covered:
This review provides a comprehensive landscape of ocular LAII drug delivery technologies with clinical precedent, including eight commercial products and 27 clinical programs. Analysis of this landscape, and the specific technologies with the greatest precedent, provides instructive lessons for researchers interested in this space and insights into the direction of the field.
Expert opinion:
Further technological advancement is required to create biodegradable LAIIs with extended release durations and LAIIs that are compatible with a broader array of therapeutic modalities. In the future, ocular LAII innovations can be applied to diseases with limited treatment options, prophylactic treatment at earlier stages of disease, and cost-effective treatment of ocular diseases in global health settings.
A computational model is proposed to investigate drug delivery systems in which erosion and diffusion mechanisms are participating in the drug release process. Our approach allowed us to analytically estimate the crossover point between those mechanisms through the value of the parameter b (b_{c}=1) and the scaling behavior of parameter τ on the Weibull function, exp[-(t/τ)^{b}], used to adjust drug release data in pharmaceutical literature. Numerical investigations on the size dependence of the characteristic release time τ found it to satisfy either linear or quadratic scaling relations on either erosive or diffusive regimes. Along the crossover, the characteristic time scales with the average coefficient observed on the extreme regimes (i.e., τ∼L^{3/2}), and we show that this result can be derived analytically by assuming an Arrhenius relation for the diffusion coefficient inside the capsule. Based on these relations, a phenomenological expression for the characteristic release in terms of size L and erosion rate κ is proposed, which can be useful for predicting the crossover erosion rate κ_{c}. We applied this relation to the experimental literature data for the release of acetaminophen immersed in a wax matrix and found them to be consistent with our numerical results.
Management, Analysis, and Simulation of Micrographs with Cloud Computing - Volume 27 Issue 2 - Shawn Zhang, Alan P. Byrnes, Jasna Jankovic, Joseph Neilly
Poly(D,L-lactic-co-glycolic acid) (PLGA)/poly (lactic acid) (PLA) microspheres/nanoparticles are one of the most successful drug delivery systems (DDS) in lab and clinic. Because of good biocompatibility and biodegradability, they can be used in various areas, such as longterm release system, vaccine adjuvant, tissue engineering, etc. There have been 15 products available on the US market, but the system still has many problems during development and manufacturing, such as wide size distribution, drug stability issues, and so on. Recently, many new and modified methods have been developed to overcome the above problems. Some of the methods are easy to scale up, and have been available on the market to achieve pilot scale or even industrial production scale. Furthermore, the relevant FDA guidance on the DDS is still incomplete, especially for abbreviated new drug application. In this review, we present some recent achievement of the PLGA/PLA microspheres/nanoparticles, and discuss some promising manufacturing methods. Finally, we focus on the current FDA guidance on the DDS. The review provides an overview on the development of the system in pharmaceutical industry.
Diesel engine exhaust aftertreatment components, especially the diesel particulate filter (DPF), are subject to various modes of degradation over their lifetimes. One particular adverse effect on the DPF is the significant rise in pressure drop due to the accumulation of engine lubricant-derived ash which coats the inlet channel walls effectively decreasing the permeability of the filter. The decreased permeability due to ash in the DPF can result in increased filter pressure drop and decreased fuel economy. A unique two-step approach, consisting of experimental measurements and direct numerical simulations using ultra-high resolution 3D imaging data, has been utilized in this study to better understand the effects of ash accumulation on engine aftertreatment component functionality. In this study, ash permeability was directly measured on the surface of ceramic (cordierite) wafers as a function of ash type (field ash, lab-generated and with chemical/morphological variations) and packing density. Ultra-high resolution X-ray Computed Tomography (CT) with a transmission X-ray source (voxel size ~500nm) was utilized for direct and accurate 3D visualization of the catalyst substrate structure, the individual ash particles (which have an average size of 1-2µm) and the ash which penetrates into the substrate surface pores. In combination with CT data deep image analysis, a new generation of direct numerical simulation algorithms (solving Naiver-Stokes equations efficiently for imaging data with billions of voxels) is used to compute permeability of the combined ash/washcoat/substrate system directly from the 3D CT images. This study discusses the sample preparations necessary for high CT resolution, the combination of CT data and deep image processing for permeability calculations, the comparison between calculated and experimentally measured permeability values and the implications of the ability to calculate accurate permeability values in the combined ash-catalyst substrate system.
Image analysis and numerical simulation algorithms are introduced to analyze the micro-structure, transport, and electrochemical performance of thin, low platinum loading inkjet printed electrodes. A local thresholding algorithm is used to extract the catalyst layer pore morphology from focused ion beam scanning electron microscopy (FIB-SEM) images. n-point correlation functions, such as auto-correlation, chord length, and pore-size distribution are computed to interpret the micro-structure variations between different images of the same catalyst layer. Pore size distributions are in agreement with experimental results. The catalyst layer exhibits anisotropy in the through-plane direction, and artificial anisotropy in the FIB direction due to low slicing resolution. Microscale numerical mass transport simulations show that transport predictions are affected by image resolution and that a minimum domain size of 200 nm is needed to estimate transport properties. A micro-scale electrochemical model that includes a description of the ionomer film resistance and a multi-step electrochemical reaction model for the oxygen reduction reaction is also presented. Results show that the interfacial mass transport resistance in the ionomer film has the largest effect on the electrochemical performance.
In-vitro degradation of 50/50 PLGA for programmed drug release has been systematically investigated from the drug eluting stents. Mass loss, molecular weight reduction, thermal changes and surface morphology of the drug eluting stents were analyzed as a function of degradation time. It was observed that degradation of 50/50 PLGA occurs in two phases. Quick decrease in molecular weight but little mass loss took place during first phase whereas in second phase, molecular weight reduction is slow with significant mass loss. This phenomenon supports heterogeneous degradation mechanism of PLGA. Drug release was attributed to diffusion rather then polymer degradation.
In past two decades poly lactic-co-glycolic acid (PLGA) has been among the most attractive polymeric candidates used to fabricate devices for drug delivery and tissue engineering applications. PLGA is biocompatible and biodegradable, exhibits a wide range of erosion times, has tunable mechanical properties and most importantly, is a FDA approved polymer. In particular, PLGA has been extensively studied for the development of devices for controlled delivery of small molecule drugs, proteins and other macromolecules in commercial use and in research. This manuscript describes the various fabrication techniques for these devices and the factors affecting their degradation and drug release.
Poly(D,L-lactic-co-glycolic acid) (PLGA) is the most frequently used biodegradable polymer in the controlled release of encapsulated drugs. Understanding the release mechanisms, as well as which factors that affect drug release, is important in order to be able to modify drug release. Drug release from PLGA-based drug delivery systems is however complex. This review focuses on release mechanisms, and provides a survey and analysis of the processes determining the release rate, which may be helpful in elucidating this complex picture. The term release mechanism and the various techniques that have been used to study release mechanisms are discussed. The physico-chemical processes that influence the rate of drug release and the various mechanisms of drug release that have been reported in the literature are analyzed in this review, and practical examples are given. The complexity of drug release from PLGA-based drug delivery systems can make the generalization of results and predictions of drug release difficult. However, this complexity also provides many possible ways of solving problems and modifying drug release. Basic, generally applicable and mechanistic research provides pieces of the puzzle, which is useful in the development of controlled-release pharmaceuticals.
The Ozurdex(®) (Allergan Inc., Irvine, CA, USA) dexamethasone drug delivery system (DDS) was recently developed as a biodegradable intravitreal implant to provide sustained delivery of 700 μg of preservativefree dexamethasone to the retina and vitreous, and is approved by the United States Food and Drug Administration (FDA) for the treatment of macular edema associated with retinal vein occlusion, as well as for noninfectious posterior uveitis. This review summarizes the rationale behind the development of the dexamethasone DDS, evidence for its use in various clinical scenarios, and compares its efficacy to other available treatment options.
Published data regarding the dexamethasone DDS as well as unpublished data that has been presented at national meetings were reviewed.
The dexamethasone DDS has evidence for efficacy in multiple clinical situations, including macular edema associated with retinal vein occlusion (RVO), macular edema associated with uveitis or Irvine-Gass syndrome, diabetic macular edema in vitrectomized eyes, persistent macular edema, noninfectious vitritis, and as adjunctive therapy for age-related macular degeneration. Safety concerns include cataract formation and intraocular pressure elevation that is most often temporary and amenable to medical management.
The dexamethasone DDS is one of the most recent additions to the armamentarium against macular edema, and is intriguing for its potency, dose consistency, potential for extended duration of action, and favorable safety profile. Early evidence shows clinical utility for several conditions, the most well established being for macular edema associated with RVO. Future studies and, in particular, head-to-head comparisons with other treatment modalities will elucidate the precise role for the dexamethasone DDS in clinical practice.
Nonadherence to antipsychotic medications is a major obstacle preventing optimal outcomes for patients with schizophrenia. Extended release systems exist in the form of depot injections, but these formulations exhibit several disadvantages. To address these concerns, we previously demonstrated proof of concept for an antipsychotic implant containing risperidone and the biodegradable polymer poly(lactic-co-glycolic) acid (PLGA).
We build upon recently published data by utilizing a scalable single-screw extrusion system for the production of PLGA-risperidone implants. Implants were composed of 40% risperidone and 60% PLGA, with varying ratios of lactide to glycolide (50:50, 65:35, 75:25 or 85:15). Risperidone release was assessed in vitro and in vivo in rats, and Level A, B and C correlations (IVIVCs) attempted for all. Bioavailability was verified with locomotor testing
Level B analysis yielded the greatest correlation between in vitro and in vivo data (R (2) = 0.9425), while Level C yielded the lowest (R (2) = 0.8336). Although, based on qualitative results, a Level A correlation was not achieved, it did produce an R (2) of 0.9261. Locomotor testing demonstrated that peak serum concentrations coincide with significant reductions in activity.
Data demonstrate the applicability of our modeling system and advance long-term, implantable antipsychotics toward clinical application.
The advancement in material design and engineering has led to the rapid development of new materials with increasing complexity and functions. Both non-degradable and degradable polymers have found wide applications in the controlled delivery field. Studies on drug release kinetics provide important information into the function of material systems. To elucidate the detailed transport mechanism and the structure-function relationship of a material system, it is critical to bridge the gap between the macroscopic data and the transport behavior at the molecular level.
The structure and function information of selected non-degradable and degradable polymers have been collected and summarized from literature published after the 1990s. The release kinetics of selected drug compounds from various material systems is discussed in case studies. Recent progress in the mathematical models based on different transport mechanisms is highlighted.
This article aims to provide an overview of structure-function relationships of selected non-degradable and degradable polymers as drug delivery matrices.
Understanding the structure-function relationship of the material system is key to the successful design of a delivery system for a particular application. Moreover, developing complex polymeric matrices requires more robust mathematical models to elucidate the solute transport mechanisms.
Long-acting implants are typically formulated using carrier(s) with specific physical and chemical properties, along with the active pharmaceutical ingredient (API), to achieve the desired daily exposure for the target duration of action. In characterizing such formulations, real-time in-vitro and in-vivo experiments that are typically used to characterize implants are lengthy, costly, and labor intensive as these implants are designed to be long acting. A novel characterization technique, combining high resolution three-dimensional X-Ray microscopy imaging, image-based quantification, and transport simulation, has been employed to provide a mechanistic understanding of formulation and process impact on the microstructures and performance of a polymer-based implant. Artificial intelligence-based image segmentation and image data analytics were used to convert morphological features visualized at high resolution into numerical microstructure models. These digital models were then used to calculate key physical parameters governing drug transport in a polymer matrix, including API uniformity, API domain size, and permeability. This powerful new tool has the potential to advance the mechanistic understanding of the interplay between drug-microstructure and performance and accelerate the therapeutic development long-acting implants.
Mass transport mechanisms of drug release inside a pellet formulation through polymer membrane were investigated with focused ion beam scanning electron microscopy (FIB-SEM). Through careful control of imaging conditions, sub-surface cross sectional images were acquired on two controlled release membrane samples. Image analysis of porosity, pore size distribution, and pore connectivity in 3D provided a matrix of parameters to quantitatively compare samples from different formulations and processing conditions. Image-based computational fluid dynamics simulations were employed to correlate membrane microporosity with flow permeability. Through high resolution FIB-SEM characterization, quantitative microporosity analysis, and mechanistic investigations of flow via image-based simulations, it was found that a 10% difference in the water content of the mixed aqueous-organic solvent used to dissolve polymers had a significant impact on the controlled release performance. This approach provides an analytical avenue to evaluate effects of permeation enhancers, solvents, and other process conditions on controlled release formulations.
Spray drying is commonly used to produce amorphous solid dispersions (ASD) to improve the bioperformance of poorly water-soluble drugs. In this study, imaging techniques such as focused ion beam-scanning electron microscopy (FIB-SEM) and X-ray microcomputed tomography (XRCT) were used to study the microstructure of spray dried (SD) particles. Spray drying at higher outlet temperature (Tout) was found to produce more spherical hollow particles with smooth surface and thinner walls, while more raisin-like particles with thicker walls were generated at lower Tout. For the first time, an artificial intelligence–facilitated XRCT image analysis tool was developed to make quantitative analysis of thousands of particles individually possible. The particle size distribution through XRCT image analysis is generally in line with what is measured by laser diffraction. The image analysis reveals envelope density as a more sensitive physical attribute for process change than conventional bulk/tap density. Further, the tensile strength of SD particle compacts correlates with the particle wall thickness, and this is likely caused by the larger interparticle contact area generated by more deformation of particles with thinner walls. The knowledge gained here can help enable SD particle engineering and drug product with more robust process and optimized performance.
For polymer-based controlled release drug products (e.g. microspheres and implants), active pharmaceutical ingredient distribution and microporosity inside the polymer matrix are critical for product performance, particularly drug release kinetics. Due to the decreasing domain size and increasing complexity of such products, conventional characterization and release test techniques are limited by their resolution and speed. In this study, samples of controlled release poly(lactic-co-glycolic acid) microspheres in the diameter range of 30–80 μm are investigated with focused ion beam scanning electron microscope imaging at 20 nm or higher resolution. Image data is quantified with artificial intelligence-based image analytics to provide size distributions of drug particles and pores within the microsphere sample. With an innovative image-based numerical simulation method, release profiles are predicted in a matter of days regardless of the designed release time. A mechanistic understanding on the impact of porosity to the interplays of drug, formulation, process, and dissolution was gained.
Carrier-based dry powder inhaler (DPI) formulations need to be accurately characterised for their particle size distributions, surface roughnesses, fines contents and flow properties. Understanding the micro-structure of the powder formulation is crucial, yet current characterisation methods give incomplete information. Commonly used techniques like laser diffraction (LD) and optical microscopy (OM) are limited due to the assumption of sphericity and can give variable results depending on particle orientation and dispersion. The aim of this work was to develop new powder analytical techniques using X-ray computed tomography (XCT) that could be employed for non-destructive metrology of inhaled formulations. α-lactose monohydrate powders with different characteristics have been analysed, and their size and shape (sphericity/aspect ratio) distributions compared with results from LD and OM. The three techniques were shown to produce comparable size distributions, while the different shape distributions from XCT and OM highlight the difference between 2D and 3D imaging. The effect of micro-structure on flowability was also analysed through 3D measurements of void volume and tap density. This study has demonstrated for the first time that XCT provides an invaluable, non-destructive and analytical approach to obtain number- and volume-based particle size distributions of DPI formulations in 3D space, and for unique 3D characterisation of powder micro-structure.
Iterative Machine Learning Method for Pore-Back Artifact Mitigation in High Porosity Membrane FIB-SEM Image Segmentation - Volume 25 Supplement - Joseph Tracey, Sam Sheng Lin, Jasna Jankovic, Aiden Zhu, Shawn Zhang
Transport properties, performance, and durability of a proton exchange fuel cell (PEMFC) highly depend on microstructure and spatial distribution of components in the gas diffusion layer (GDL), microporous layer (MPL), and catalyst layers (CLs) of the fuel cell. Modeling of transport properties and understanding of these effects are challenging due to limited understanding of actual three-dimensional (3D) structure of the components, especially over a wide range of length scales. In this work, 3D imaging on multiple scales, namely electron tomography on a nanoscale, focused ion beam-scanning electron microscopy on a microscale, and 3D X-ray microscopy on a macroscale, was applied to obtain 3D reconstructions of the actual CL, MPL, and GDL microstructure. Direct numerical simulations on 3D data sets with an upscaling approach were applied to demonstrate the capability to simulate overall electrical conductivity of the system. Details of the process, challenges, and results are described.
Fresh cores from tight-rock samples of subsurface hydrocarbon reservoirs retain mobile fluids. These fluids have complex chemical compositions and a large spectrum of molecules with different diameters and polarities. When investigated using highresolution field-emission scanning electron microscopy (SEM), the imposed vacuum over hours of time causes pore fluids trapped in the rock sample to flow and interact with the mineral matrix. This paper reports the capillary fluid dynamics effect observed on freshly milled cross sections of tight chalk at high resolution. Multiphase fluid dynamic simulations confirm the aggregation of heavier fluid molecules on the geometrical irregularities of the pore space. As a consequence of this pitfall, the differentiation of solid organic matter versus variably viscous hydrocarbons from SEM data is subject to a fundamental revision. Copyright © 2017. The American Association of Petroleum Geologists. All rights reserved.
This book approaches the subject from a mechanistic perspective that pitches the language at a level that is understandable to those entering the field and who are not familiar with its common phrases or complex terms. It provides a simple encapsulation of concepts and expands on them. In each chapter the basic concept is explained as simply and clearly as possible without a great deal of detail, then in subsequent sections additional material, exceptions to the general rule, examples, etc., is introduced and built up. Such material was generously supplemented with diagrams; conceptually elegant line diagrams in two or three colors. The artwork was well thought out and able to condense the scientific principles into a novel and visually exciting form. The diagrams encourage browsing or draw the reader to salient points. In addition, the technique of highlighting key concepts in a separate box is used throughout each chapter.
The potential for use of polymers in controlled drug delivery systems has been long recognized. Since their appearance in the literature, a wide range of degradable and non-degradable polymers have been demonstrated in drug delivery devices.
The significance and features of ethylene-vinyl acetate (EVA) copolymers in initial research and development led to commercial drug delivery systems. This review examines the breadth of EVA use in drug delivery, and will aid the researcher in locating key references and experimental results, as well as understanding the features of EVA as a highly versatile, biocompatible polymer for drug delivery devices.
Topics will include
A. Delivery systems - transdermal, implants, such as transmucosal, vaginal, subcutaneous, ocular, brain, and coatings.
B. Fundamental studies – drug elution, API types (small molecules, biologics, combinations).
C. Commercial & predicate use of durable polymers in drug delivery devices, focused on EVA.
A complete description of the particle formation process can only be realized with techniques that enable the measurement of the composition and structural dependence of individual particles.
The purpose of this publication is to highlight the utility of one such high resolution imaging technique; focused-ion scanning electron microscopy (FIB-SEM). As a model system, amorphous dispersion particles of felodipine and polyvinylpyrrolidone (PVP) were prepared by spray drying and used to interrogate single particles. Further, FIB-SEM was coupled with energy dispersive X-ray analysis (EDX) to characterize spatial chemical distributions in spray dried amorphous solid dispersion particles. Within a single spray drying batch, individual particles exhibited different phase behavior as a function of particle size. Larger particles showed notable amorphous-amorphous phase separation while smaller particles showed uniform composition. The morphology of particles was also found to be a function of particle size. Larger particles were consistently more porous in nature compared to smaller particles. The observed differences in compositional heterogeneity of different spray dried particles as a function of size are interpreted via theoretical arguments based on the Peclet number, the ratio of the evaporative flux of the solvent to the diffusive flux of the drug and the polymer within the droplet. Phase behavior may also be interpreted in terms of equilibrium ternary phase diagrams. Regardless, commonly used bulk physical and chemical characterization techniques may be used to establish correlations between the nature of the dispersion and the processing parameters. However, these techniques lack the resolution to provide a scientific link between the processing conditions and the nature of individual particles. The current paper highlights the utility of high resolution morphological and compositional measurements of individual particles.
Data Mining: Practical Machine Learning Tools and Techniques, Fourth Edition, offers a thorough grounding in machine learning concepts, along with practical advice on applying these tools and techniques in real-world data mining situations. This highly anticipated fourth edition of the most acclaimed work on data mining and machine learning teaches readers everything they need to know to get going, from preparing inputs, interpreting outputs, evaluating results, to the algorithmic methods at the heart of successful data mining approaches. Extensive updates reflect the technical changes and modernizations that have taken place in the field since the last edition, including substantial new chapters on probabilistic methods and on deep learning. Accompanying the book is a new version of the popular WEKA machine learning software from the University of Waikato. Authors Witten, Frank, Hall, and Pal include today's techniques coupled with the methods at the leading edge of contemporary research. Please visit the book companion website at http://www.cs.waikato.ac.nz/ml/weka/book.html It contains Powerpoint slides for Chapters 1-12. This is a very comprehensive teaching resource, with many PPT slides covering each chapter of the book Online Appendix on the Weka workbench; again a very comprehensive learning aid for the open source software that goes with the book Table of contents, highlighting the many new sections in the 4th edition, along with reviews of the 1st edition, errata, etc. Provides a thorough grounding in machine learning concepts, as well as practical advice on applying the tools and techniques to data mining projects Presents concrete tips and techniques for performance improvement that work by transforming the input or output in machine learning methods Includes a downloadable WEKA software toolkit, a comprehensive collection of machine learning algorithms for data mining tasks-in an easy-to-use interactive interface Includes open-access online courses that introduce practical applications of the material in the book.
Hydrogel delivery systems can leverage therapeutically beneficial outcomes of drug delivery and have found clinical use. Hydrogels can provide spatial and temporal control over the release of various therapeutic agents, including small-molecule drugs, macromolecular drugs and cells. Owing to their tunable physical properties, controllable degradability and capability to protect labile drugs from degradation, hydrogels serve as a platform on which various physiochemical interactions with the encapsulated drugs occur to control drug release. In this Review, we cover multiscale mechanisms underlying the design of hydrogel drug delivery systems, focusing on physical and chemical properties of the hydrogel network and the hydrogel–drug interactions across the network, mesh and molecular (or atomistic) scales. We discuss how different mechanisms interact and can be integrated to exert fine control in time and space over drug presentation. We also collect experimental release data from the literature, review clinical translation to date of these systems and present quantitative comparisons between different systems to provide guidelines for the rational design of hydrogel delivery systems.
The objective of this study was development of accelerated in vitro release method for peptide loaded PLGA microspheres using flow-through apparatus and assessment of the effect of dissolution parameters (pH, temperature, medium composition) on drug release rate and mechanism. Accelerated release conditions were set as pH 2 and 45°C, in phosphate buffer saline (PBS) 0.02M. When the pH was changed from 2 to 4, diffusion controlled phases (burst and lag) were not affected, while release rate during erosion phase decreased two-fold due to slower ester bonds hydrolyses. Decreasing temperature from 45°C to 40°C, release rate showed three-fold deceleration without significant change in release mechanism. Effect of medium composition on drug release was tested in PBS 0.01M (200 mOsm/kg) and PBS 0.01M with glucose (380 mOsm/kg). Buffer concentration significantly affected drug release rate and mechanism due to the change in osmotic pressure, while ionic strength did not have any effect on peptide release. Furthermore, dialysis sac and sample-and-separate techniques were used, in order to evaluate significance of dissolution technique choice on the release process. After fitting obtained data to different mathematical models, flow-through method was confirmed as the most appropriate for accelerated in vitro dissolution testing for a given formulation.
Lipid-based lyotropic liquid crystals, also referred to as reversed liquid crystalline mesophases, such as bicontinuous cubic, hexagonal or micellar cubic phases, have attracted deep interest in the last few decades due to the possibility of observing these systems at thermodynamic equilibrium in excess water conditions. This becomes of immediate significance for applications in the colloidal environment, such as in the food, cosmetic and pharmaceutical arenas. One possible application regarded as very promising is that of controlled delivery of functional ingredients. Different crystallographic structures of the lipid mesophase give access to different diffusion coefficients and distinct diffusion modes. It becomes thus crucial to engineer the space group of the mesophase in a controlled way, and ideally, in a stimuli-responsive manner. In this article we review the state of the art on diffusion and molecular transport in lipid-based mesophases and we discuss recent contributions to the controlled delivery of molecules and colloids through these systems. In particular we focus on the different available strategies relying on either endogenous or exogenous stimuli to induce changes in the symmetry and transport properties of lipid-based mesophases and we discuss the impact and implications this may have on controlled drug delivery.
Microemulsions (MEs) have been studied extensively as colloidal carriers for the delivery of both water-soluble and lipid-soluble drugs. Our previous study showed that addition of water to ME formulations resulted in phase transition to either liquid crystal (LC) or coarse emulsion (CE). The aim of this study was to investigate whether these MEs could be used as drug delivery vehicles for prolonged release through in-situ phase transition following extravascular injection. Three ME formulations from the same pseudo-ternary phase diagram were investigated with respect to their phase transition behavior, and in-vivo drug release; a coarse emulsion-forming ME (CE-ME), an oil rich LC-forming ME (LC-ME1), and an oil poor LC-forming ME (LC-ME2). CE-ME was a W/O ME and both LC-MEs were O/W type. The release profiles of (99m)Tc labeled MEs following subcutaneous (SC) injection in rabbits were investigated with gamma-scintigraphy. The CE-ME dispersed readily in water, forming a CE, whereas the LC-forming MEs formed 'depots' in water. Polarized microscopy revealed a LC boundary spontaneously formed at the water/ME interface for the LC-MEs with the LC-ME2 forming a substantially thicker LC layer. The CE resulting from the water-induced transition of the CE-forming ME had a higher viscosity than the MEs, but lower than the LCs resulted from LC-MEs. Compared to LC-ME1, LC-ME2 underwent more rapid phase transition and the resultant LC had significant higher viscosity. The LCs formed from both ME formulations exhibited pseudoplastic properties; increasing the shear rate decreased the apparent viscosity exponentially. Following SC injection into the animal thigh, the LC-MEs had more prolonged release of (99m)Tc in a first-order manner, than CE-ME. The oil poor LC-ME2 had the slowest release with a t1/2 of 77min, 2.1 times longer than the oil rich LC-ME1; consistent with the thickness of LC layer formation observed in-vitro and their relative viscosities. In conclusion, the present in-vivo study has demonstrated the application of MEs as extravascular injectable drug delivery systems for sustained release. The retention of the vehicles at the injection site and the release rate were determined predominantly by their phase transition rather than ME type or oil content.
PLGA microspheres are widely studied for controlled release drug delivery applications, and many models have been proposed to describe PLGA degradation and erosion and drug release from the bulk polymer. Autocatalysis is known to have a complex role in the dynamics of PLGA erosion and drug transport and can lead to size-dependent heterogeneities in otherwise uniformly bulk-eroding polymer microspheres. The aim of this review is to highlight mechanistic, mathematical models for drug release from PLGA microspheres that specifically address interactions between phenomena generally attributed to autocatalytic hydrolysis and mass transfer limitation effects. Predictions of drug release profiles with mechanistic models are useful for understanding mechanisms and designing drug release particles.
Mathematical modeling of drug release can be very helpful to speed up product development and to better understand the mechanisms controlling drug release from advanced delivery systems. Ideally, in silico simulations can quantitatively predict the impact of formulation and processing parameters on the resulting drug release kinetics. The aim of this article is to give an overview on the current state of the art of modeling drug release from delivery systems, which are predominantly controlled by diffusional mass transport. The inner structure of the device, the ratio "initial drug concentration:drug solubility" as well as the device geometry determine which type of mathematical equation must be applied. A straightforward "road map" is given, explaining how to identify the appropriate equation for a particular type of drug delivery system. The respective equations for a broad range of devices are indicated, including reservoir and matrix systems, exhibiting or not an initial excess of drug and the geometry of slabs, spheres and cylinders. The assumptions the models are based on as well as their limitations are pointed out. Practical examples illustrate the usefulness of mathematical modeling of diffusion controlled drug delivery. Due to the advances in information technology the importance of in silico optimization of advanced drug delivery systems can be expected to significantly increase in the future.
The safety and effectiveness of systemic and topical medical therapies for ocular disorders are limited due to poor ocular drug uptake, nonspecificity to target tissues, systemic side effects, and poor adherence to therapy. Intravitreal injections can enhance ocular drug delivery, but the need for frequent retreatment and potential injection-related side effects limit the utility of this technique. Sustained-release drug delivery systems have been developed to overcome these limitations; such systems can achieve prolonged therapeutic drug concentrations in ocular target tissues while limiting systemic exposure and side effects and improving patient adherence to therapy. A critical factor in the development of safe and effective drug delivery systems has been the development of biocompatible polymers, which offer the versatility to tailor drug release kinetics for specific drugs and ocular diseases. Ocular implants include nonbiodegradable and biodegradable designs, with the latter offering several advantages. The polymers most commonly used in biodegradable delivery systems are synthetic aliphatic polyesters of the poly-α-hydroxy acid family including polylactic acid, polyglycolic acid, and polylactic-co-glycolic acid. The characteristics of these polymers for medical applications as well as the pharmacological properties, safety, and clinical effectiveness of biodegradable drug implants for the treatment of ocular diseases are reviewed herein.
A series of matrix-type drug delivery devices comprising a continuous phase of microporous poly(epsilon-caprolactone) (PCL) and a dispersed phase of protein particles (gelatin) with defined size ranges (45-90, 90-125 and 125-250 microm) were produced by rapidly cooling suspensions in dry ice followed by solvent extraction from the hardened material. High protein loadings (38-44%, w/w) were achieved and highly efficient protein release (90% of the initial load) was obtained over time periods of 3-11 days depending on particle loading and size range. The duration of protein release was extended from 3 to 11 days by reducing the protein load. Quantitative analysis of Micro-CT images identified a three to four times increase in the population of sub-40 microm pores in those matrices which gave rise to accelerated protein release in 24 h (40% rising to 80%) and reduced duration of protein release (11-3 days). Formation of a high density of channels and fissures (connects) between the particles is indicated, which facilitate fluid ingress and diffusion of solubilised protein molecules. Micro-CT analysis also confirmed the uniformity of particle distribution in the matrices and provided measurements of macroporosity within 5-30% of the theoretical value for materials displaying irregular shaped macropores larger than 90 microm. These findings demonstrate the utility of Micro-CT for optimising the formulation and performance of matrix-type delivery devices for macromolecular entities.
This paper describes the earliest days when the “controlled drug delivery” (CDD) field began, the pioneers who launched this exciting and important field, and the key people who came after them. It traces the evolution of the field from its origins in the 1960s to (a) the 1970s and 1980s, when numerous macroscopic “controlled” drug delivery (DD) devices and implants were designed for delivery as mucosal inserts (e.g., in the eye or vagina), as implants (e.g., sub-cutaneous or intra-muscular), as ingestible capsules (e.g., in the G-I tract), as topical patches (e.g., on the skin), and were approved for clinical use, to (b) the 1980s and 1990s when microscopic degradable polymer depot DD systems (DDS) were commercialized, and to (c) the currently very active and exciting nanoscopic era of targeted nano-carriers, in a sense bringing to life Ehrlich's imagined concept of the “Magic Bullet”. The nanoscopic era began with systems proposed in the 1970s, that were first used in the clinic in the 1980s, and which came of age in the 1990s, and which are presently evolving into many exciting and clinically successful products in the 2000s. Most of these have succeeded because of the emergence of three key technologies: (1) PEGylation, (2) active targeting to specific cells by ligands conjugated to the DDS, or passive targeting to solid tumors via the EPR effect.
In the past few years, an increasing number of in situ-forming systems have been reported in the literature for various biomedical applications, including drug delivery, cell encapsulation, and tissue repair. There are several possible mechanisms that lead to in situ gel formation: solvent exchange, UV-irradiation, ionic cross-linkage, pH change, and temperature modulation. The thermosensitive approach can be advantageous for particular applications as it does not require organic solvents, co-polymerization agents, or an externally applied trigger for gelation. In the last 2 decades, several thermosensitive formulations have been proposed. This manuscript focuses on aqueous polymeric solutions that form implants in situ in response to temperature change, generally from ambient to body temperature. It mainly reviews the characterization and use of polysaccharides, N-isopropylacrylamide copolymers, poly(ethylene oxide-b-propylene oxide-b-ethylene oxide) (poloxamer) and its copolymers, poly(ethylene oxide)/(D,L-lactic acid-co-glycolic acid) copolymers, and thermosensitive liposome-based systems.
This review presents current methods and strategies for studying the release characteristics of drugs from subcutaneous implant dosage forms. Implants are dosage forms that are subcutaneously placed with the aid of surgery or a hypodermic needle, and are designed to release drugs over a prolonged period of time. In most cases, the objective of a release test is to identify sufficiently discriminatory procedures that in turn would provide data to set meaningful specifications. Additional information obtained from successful in vitro–in vivo correlations (IVIVC) and accelerated drug release tests are extremely useful during drug product development.
Although several workers have employed different methods to monitor drug release from these dosage forms, the use of the compendial Apparatus 4 (flow-through) device has been recommended in a publication on FIP/AAPS Guidelines for drug release testing of modified release dosage forms. However, most of method development with this device has focused on oral immediate or controlled release dosage forms and little published information is available on implants. Two recent reports on workshops provide useful information on methods to evaluate drug release from controlled-release parenterals such as implants, including IVIVC and accelerated release testing. Details on such studies, however, are generally not found in the literature; possibly because of the high proprietary value of methodologies for establishing release specifications of implant dosage forms. This article reviews the current status of methodologies used in the investigation of drug release from subcutaneous implants with an emphasis on mechanistic, product development and regulatory perspectives. Copyright
Here we investigated the possibility to develop different levels of correlation between in vitro drug release profiles and in vivo pharmacokinetic parameters for three Buserelin implant formulations. The in vitro and in vivo data were analyzed using model-independent and model-dependent methods. Since diffusion, dissolution and erosion effects influence drug release in most cases a simple kinetic model is unlikely to explain the overall in vivo release behavior. Thus the in vitro drug release curves were analyzed according to the theoretical models of Higuchi and Korsmeyer-Peppas. For the formulation with predominant diffusion controlled release level A IVIVC could be established (R2=0.986). Independent on drug release mechanism, a level B correlation between the mean in vitro dissolution time (MDT) and mean in vivo residence time (MRT) was obtained with a correlation coefficient of 0.983. Finally, level C correlation were observed when single in vitro parameters, e.g. T50% (time required to release 50% of drug in vitro) where compared with single in vivo parameters like AUC. This study suggests that a level B correlation could be achieved even when drug release occurs by a combination of diffusion and erosion processes. More sophisticated in vitro models mimicking drug release under in vivo conditions are clearly desirable for parenteral depot formulations.
System and method for computing drug controlled release performance using images. US Provisional Application No. 62/569.021, 10/6/2017
- S Zhang
Correlative focused ion beam scanning electron microscope and x-ray micro-computed tomography imaging on multi-scale drug release characterization and 3D-printing manufacturing
- Zhang
System and Method to Predict Mass Transport from Complex Release Systems Using Data-based Modeling
- S Zhang
System and Method to Predict Mass Transport from Complex Release Systems Using Experimental Data-based Modeling
- Zhang
Reconstruction of Thin Wall Features Marginally Resolved by Multi-Dimensional Images. US Provisional Patent Application Number: 62994603
- S Zhang
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In vitro and in vivo correlation of buserelin release from biodegradable implants using statistical moment analysis.
- Schliecker G
- Schmidt C
- Fuchs S
- Ehinger A
- Sandw J
- Kissel T