The Effects of Applied Local Heat on Transdermal Drug Delivery Systems

Transdermal drug delivery systems have been developed over the past several decades and now include patches for birth control, nicotine addiction, and pain relief. The local application of heat can increase the diffusion coefficient of the drug in the skin and result in faster delivery of the drug and shorter time to reach a steady state concentration of the drug. While this procedure is desirable for some systems where a faster dose will aid in alleviating pain and/or symptoms, it can also be a cause of concern for some drugs. Fentanyl, a chronic pain relief drug, can cause accidental death by overdose. We report herein an analysis of the effects of various heating situations on transdermal fentanyl delivery based upon a model developed using COMSOL Multiphysics. The utilization of such a model allows for the determination of situations which may be potentially dangerous for fentanyl drug users, and enables the development of usage guidelines and safety mechanisms for transdermal delivery systems. Using the computer model, the following cases were simulated: no applied heat, ThermaCare heat pad, fever, and heating blanket. The heating blanket and ThermaCare heat pad simulations showed the most dangerous increases in fentanyl blood concentration above no-heat levels: about 180% and 100%, respectively, over 30 hours; by contrast, the patient fever model reported a 40% increase in fentanyl blood concentration. These simulations demonstrate the dangers of fentanyl transdermal pain patches when skin temperature is increased, and can be used to develop better patient guidelines for patch use and to improve fentanyl transdermal systems. Lastly, this computer model may be used to model other transdermal drug delivery systems for the improvement of patient guidelines and/or the development of new systems, thus decreasing the need for experimentation on subjects

Nanoscale Drug Delivery Vehicles Based on Poly(ester amide)s

Poly(ester amide)s (PEA)s offer several properties superior to currently used systems such as fewer acidic degradation products and functional handles for the conjugation of bioactive molecules. Herein, two novel PEA based drug delivery systems were developed and evaluated. The first utilizes PEAs containing pendant carboxylic acid functional groups and was evaluated with respect to its ability to control the release of a model drug, a Rhodamine B derivative. The drug exhibited sustained release without a burst phase, demonstrating the utility of the carboxylic functional handles. A second drug delivery system was prepared utilizing novel polyethylene oxide)-PEA copolymers which formed into micelles. The resulting system was capable of encapsulating and releasing Nile Red, a model hydrophobic drug, on a pharmacologically relevant time scale. Overall, these results suggest that PEAs are excellent biomaterials, capable of delivering therapeutics and have the potential to overcome many of the deficiencies found in current delivery systems

Diffusion-based design of multi-layered ophthalmic lenses for controlled drug release

The study of ocular drug delivery systems has been one of the most covered topics in drug delivery research. One potential drug carrier solution is the use of materials that are already commercially available in ophthalmic lenses for the correction of refractive errors. In this study, we present a diffusion-based mathematical model in which the parameters can be adjusted based on experimental results obtained under controlled conditions. The model allows for the design of multi-layered therapeutic ophthalmic lenses for controlled drug delivery. We show that the proper combination of materials with adequate drug diffusion coefficients, thicknesses and interfacial transport characteristics allows for the control of the delivery of drugs from multi-layered ophthalmic lenses, such that drug bursts can be minimized, and the release time can be maximized. As far as we know, this combination of a mathematical modelling approach with experimental validation of non-constant activity source lamellar structures, made of layers of different materials, accounting for the interface resistance to the drug diffusion, is a novel approach to the design of drug loaded multi-layered contact lenses.info:eu-repo/semantics/publishedVersio

Electrohydrodynamic Processing for Preparation of Advanced Drug Delivery Systems

This research explores the feasibility of the electrohydrodynamic processing using single and co-axial set-up as a single step processing tool for preparation of advanced drug delivery systems. A number of synthetic biodegradable and non-biodegradable polymers were used in order to prepare formulations incorporating drugs of different physicochemical characteristics. Based on the focus and the desired applications, the polymeric carrier and solvent system as well as the model drug of interest were selected to develop the drug delivery systems. Firstly, core-shell microparticles were prepared and optimized using co-axial electrohdrodynamic processing with precise control over the averaged particle size and size distribution. This was followed by integration of model drugs with different water-solubility. In this study, the release characteristics of the developed particles were investigated with single and simultaneous encapsulation of the drugs. Successful preparation of fixed dose combination formulation with high processing yield and encapsulation efficiency was reported. Secondly, single and co-axial electrohydrodynamic processing was utilized for preparation of smart drug delivery system for targeted release of prednisolone. Colon targeted drug delivery systems were developed using a pH-responsive polymer. Varying polymer drug ratio was applied to further enhance the release profiles and obtain an efficient delivery system whereby local delivery of prednisolone is made possible. Finally, microspheres were developed for co-encapsulation of anti-diabetic drugs with different water-solubility. The successfully developed sustained release formulations have the potential to overcome the existing limitations of conventional formulations by enhancing patient compliance and efficacy of the treatment of any chronic conditions

Scaling up antiretroviral therapy in Malawi-implications for managing other chronic diseases in resource-limited countries.

The national scale-up of antiretroviral therapy (ART) in Malawi is based on the public health approach, with principles and practices borrowed from the successful DOTS (directly observed treatment, short course) tuberculosis control framework. The key principles include political commitment, free care, and standardized systems for case finding, treatment, recording and reporting, and drug procurement. Scale-up of ART started in June 2004, and by December 2008, 223,437 patients were registered for treatment within a health system that is severely underresourced. The Malawi model for delivering lifelong ART can be adapted and used for managing patients with chronic noncommunicable diseases, the burden of which is already high and continues to grow in low-income and middle-income countries. This article discusses how the principles behind the successful Malawi model of ART delivery can be applied to the management of other chronic diseases in resource-limited settings and how this paradigm can be used for health systems strengthening

On adaptive control and particle filtering in the automatic administration of medicinal drugs

Automatic feedback methodologies for the administration of medicinal drugs offer undisputed potential benefits in terms of cost reduction and improved clinical outcomes. However, despite several decades of research, the ultimate safety of many--it would be fair to say most--closed-loop drug delivery approaches remains under question and manual methods based on clinicians' expertise are still dominant in clinical practice. Key challenges to the design of control systems for these applications include uncertainty in pharmacological models, as well as intra- and interpatient variability in the response to drug administration. Pharmacological systems may feature nonlinearities, time delays, time-varying parameters and non-Gaussian stochastic processes. This dissertation investigates a novel multi-controller adaptive control strategy capable of delivering safe control for closed-loop drug delivery applications without impairing clinicians' ability to make an expert assessment of a clinical situation. Our new feedback control approach, which we have named Robust Adaptive Control with Particle Filtering (RAC-PF), estimates a patient's individual response characteristic in real-time through particle filtering and uses the Bayesian inference result to select the most suitable controller for closed-loop operation from a bank of candidate controllers designed using the robust methodology of mu-synthesis. The work is presented as four distinct pieces of research. We first apply the existing approach of Robust Multiple-Model Adaptive Control (RMMAC), which features robust controllers and Kalman filter estimators, to the case-study of administration of the vasodepressor drug sodium nitroprusside and examine benefits and drawbacks. We then consider particle filtering as an alternative to Kalman filter-based methods for the real-time estimation of pharmacological dose-response, and apply this to the nonlinear pharmacokinetic-pharmacodynamic model of the anaesthetic drug propofol. We ultimately combine particle filters and robust controllers to create RAC-PF, and test our novel approach first in a proof-of-concept design and finally in the case of sodium nitroprusside. The results presented in the dissertation are based on computational studies, including extensive Monte-Carlo simulation campaigns. Our findings of improved parameter estimates from noisy observations support the use of particle filtering as a viable tool for real-time Bayesian inference in pharmacological system identification. The potential of the RAC-PF approach as an extension of RMMAC for closed-loop control of a broader class of systems is also clearly highlighted, with the proposed new approach delivering safe control of acute hypertension through sodium nitroprusside infusion when applied to a very general population response model. All approaches presented are generalisable and may be readily adapted to other drug delivery instances

Remotely triggered scaffolds for controlled release of pharmaceuticals

Fe3O4-Au hybrid nanoparticles (HNPs) have shown increasing potential for biomedical applications such as image guided stimuli responsive drug delivery. Incorporation of the unique properties of HNPs into thermally responsive scaffolds holds great potential for future biomedical applications. Here we successfully fabricated smart scaffolds based on thermo-responsive poly(N-isopropylacrylamide) (pNiPAM). Nanoparticles providing localized trigger of heating when irradiated with a short laser burst were found to give rise to remote control of bulk polymer shrinkage. Gold-coated iron oxide nanoparticles were synthesized using wet chemical precipitation methods followed by electrochemical coating. After subsequent functionalization of particles with allyl methyl sulfide, mercaptodecane, cysteamine and poly(ethylene glycol) thiol to enhance stability, detailed biological safety was determined using live/dead staining and cell membrane integrity studies through lactate dehydrogenase (LDH) quantification. The PEG coated HNPs did not show significant cytotoxic effect or adverse cellular response on exposure to 7F2 cells (p < 0.05) and were carried forward for scaffold incorporation. The pNiPAM-HNP composite scaffolds were investigated for their potential as thermally triggered systems using a Q-switched Nd:YAG laser. These studies show that incorporation of HNPs resulted in scaffold deformation after very short irradiation times (seconds) due to internal structural heating. Our data highlights the potential of these hybrid-scaffold constructs for exploitation in drug delivery, using methylene blue as a model drug being released during remote structural change of the scaffold

Silicon nanofluidic membrane for electrostatic control of drugs and analytes elution

Individualized long-term management of chronic pathologies remains an elusive goal despite recent progress in drug formulation and implantable devices. The lack of advanced systems for therapeutic administration that can be controlled and tailored based on patient needs precludes optimal management of pathologies, such as diabetes, hypertension, rheumatoid arthritis. Several triggered systems for drug delivery have been demonstrated. However, they mostly rely on continuous external stimuli, which hinder their application for long-term treatments. In this work, we investigated a silicon nanofluidic technology that incorporates a gate electrode and examined its ability to achieve reproducible control of drug release. Silicon carbide (SiC) was used to coat the membrane surface, including nanochannels, ensuring biocompatibility and chemical inertness for long-term stability for in vivo deployment. With the application of a small voltage (≤ 3 V DC) to the buried polysilicon electrode, we showed in vitro repeatable modulation of membrane permeability of two model analytes—methotrexate and quantum dots. Methotrexate is a first-line therapeutic approach for rheumatoid arthritis; quantum dots represent multi-functional nanoparticles with broad applicability from bio-labeling to targeted drug delivery. Importantly, SiC coating demonstrated optimal properties as a gate dielectric, which rendered our membrane relevant for multiple applications beyond drug delivery, such as lab on a chip and micro total analysis systems (µTAS)