Design of novel drug delivery system and optimal dosage regimens

Three representative drug delivery systems were analyzed to emphasize the roles of mathematical models and computer-aided simulations in pharmaceutical research. In the first project, a protocol was developed so that the optimal regimen, consisting of the intravenous boluses and subsequent infusion of theophylline, could be obtained once information on the pharmacokinetics became available. The method was based on a two-compartment model of the human body. A module was created and posted on a website for free access. The second project dealt with the transdermal heat-assisted delivery of corticosterone. Heat conduction and drug diffusion through the patch and the skin were expressed in the mathematical model. Four design parameters were estimated. This model was validated using clinical data from the administration of fentanyl. Cortisone concentrations through the patch and skin layers were predicted. The results were used to rank the relative impacts of the design parameters on the corticosterone delivery and to make proper suggestions for fabricating the products. Finally, the simultaneous application of an electric current and soluble microneedles were proposed for the first time. Preliminary experimental studies suggested that the electric field enhanced the flux by increasing drug diffusion and, thereby, the dissolution of the microneedles. One-, two- and three-dimensional simulations were conducted. In addition, protocols were proposed to help with the analysis of laboratory data

Modelling in vitro dissolution and release of sumatriptan succinate from polyvinylpyrrolidone-based microneedles aided by iontophoresis

A novel dissolving microneedle array system is developed to investigate permeation of a sumatriptan succinate formulations through the skin aided by iontophoresis. Three formulations consisting of hydrophilic, positively charged drug molecules encapsulated in a water-soluble biologically suitable polymer, polyvinylpyrrolidone (PVP), have been accepted by the U.S. Food and Drug Administration (FDA). The microneedle systems are fabricated with 600 pyramid-shaped needles, each 500 µm tall, on a 0.785-cm2 circular array. In vitro transdermal studies with minipig skin and vertical Franz diffusion cells show \u3e 68% permeation of sumatriptan over a 24-hour period. A combination of microneedle and electrical current density ranging from 100 to 500 µA/cm2 using Ag / AgCl electrodes displays increased flux with current density. At 500 µA/cm2, a dissolving array loaded with 4.3 mg sumatriptan leads to a steady-state delivery rate of 490 µg/cm2h with negligible lag time. In theory, a 9.58-cm2 microneedle-array patch loaded with 47.30 mg of sumatriptan succinate could provide the required plasma concentration, 72 ng/ml, for nearly six hours. In parallel, a mathematical model based on first principles is developed to predict the amount of drug delivered into the skin using software (e.g., Mathematica). A system of mass balance equations are derived to simulate the dissolution, diffusion, electromigration and transport of the active ingredient through the epidermis. The analytical approach allows for the evaluation and estimation of the effects of key parameters (i.e., loading dose, polymer concentration, needle height, needle pitch width and current density) on the release profile. The skin layer concentration increases significantly with either increased loading dose or elongated height of the microneedle. The percentage of sumatriptan permeating through skin increased favorably with increased electrical current applied to microneedle patch. An inverse correlation was observed between the pitch width (center to center distance of adjacent needles) and the cumulative amount of sumatriptan permeated into the dermis. Predicted cumulative release data from mathematical model simulations of each of the three formulations were successfully validated with in vitro permeation data administered with Franz cells and minipig skin

Novel Delivery Systems For Iron Replenishment

Iron is an integral part of hemoglobin and essential for the production of red blood cells. Iron deficiency and the resulting anemia are major nutritional deficiency disorders. The majority of patient populations suffering from iron deficiency anemia (IDA) are women of child bearing age and children of all ages. Iron deficiency is a complication of various other chronic conditions. Oral iron salts or colloidal parenteral iron formulations are treatment options for iron replenishment since several decades, but they are associated with severe side effects along with other patient noncompliance issues. Transdermal delivery of iron could be a potential alternative to treat iron deficiency due to safety and offers more acceptability. Since conventional iron formulations are not suitable for transdermal delivery, quest for an ideal iron compound resulted in identification of soluble Ferric Pyrophosphate (FPP), which was demonstrated to be very stable and safe for parenteral administration. Passive delivery of FPP was not successful due to its high molecular weight (745 Da) and low lipid solubility. Transdermal delivery of FPP using chemical permeation enhancers, iontophoresis, microneedle pretreatment and combination of these techniques were evaluated and proved to be successful in delivering iron across the skin. When iontophoresis was combined with microneedle pretreatment, adequate iron could be delivered in anemic rat models to reverse the iron deficiency. Further, a safe and patient friendly iron delivery system was developed by incorporating FPP in soluble microneedles. In vitro and in vivo studies were carried out to evaluate the FPP release and dermal kinetic profile of the iron from the soluble microneedles. Safety and toxicity of FPP in human skin cell lines was also investigated. The feasibility of transdermal delivery of Iron-dextran was also evaluated. Passive delivery of iron dextran is impossible due to its high molecular weight. Microneedle assisted delivery of iron dextran was investigated and soluble microneedle system with iron dextran was developed. Overall, the results of the project suggest that transdermal delivery of iron could be a potential alternate to treat IDA. Iron replenishment via transdermal route is likely to be more effective and safer than the conventional routes of administration

Modelling and optimization of microneedles for transdermal drug delivery

Microneedle mediated drug delivery is an amalgam of the conventional transdermal patch and the hypodermic needle injection. It offers an improved drug delivery technique without the limitations of the above methods. The ability of microneedles to increase permeability of substances in the skin has been established in the literature. However, a quantitative method for predicting the performance of microneedle devices prior to their fabrication is yet to be fully developed. The contribution of this research is a theoretical framework for modelling and optimizing microneedle array design to obtain desired drug delivery rate while taking into account the transport and mechanical properties of the skin. This is achieved by exploring various theories surrounding transdermal drug transport. The existing theories are then used to develop models to link the microneedle array design parameters with drug transport properties such as permeability and drug concentration in blood. Numerical simulations and theoretical analyses that are carried out in this PhD research indicate that microneedle design has a significant effect on drug delivery. An algorithm was developed for solving the series of equations presented, thus obtaining a framework which is applied to predict performance of microneedle arrays in vivo. Some practical scenarios are also simulated to demonstrate the applicability of the developed framework. For example, numerical simulations of transdermal delivery of Fentanyl show that varying the design parameters such as penetrated length of microneedle and the tip radius of microneedles affected the peak blood concentration. Similarly, the developed framework was used to obtain the optimum microneedle design to calculate the desired peak blood concentration similar to that obtained using conventional patch system. This study is relevant as it provides a better understanding of microneedle mediated drug delivery process and it orchestrates the design and hence, fabrication of more efficient microneedle based drug delivery devices

An arborizing, multiport catheter for maximizing drug distribution in the brain via convection enhanced delivery

Glioblastoma (GBM) is a high-grade malignant glioma with a mortality rate that exceeds 95% despite over eight decades of medical research dedicated to improve outcomes. GBM is extremely difficult to treat and practically incurable with standard treatment involving surgical resection, radiation, concomitant and/or adjuvant chemotherapy. Therefore, convection enhanced delivery (CED) was developed to improve therapeutic outcomes. CED involves intraparenchymal delivery of drugs into diseased tissue via a small catheter. CED has proven to bypass the blood brain barrier and achieve better drug distribution than diffusion-based therapies. Nevertheless, the large volumes necessary to target entire tumors and peritumor volumes have been previously unachievable with currently-available catheters. This dissertation describes the development of a multiport, arborizing catheter designed specifically for improving drug distribution in the brain. The performance of early-stage arborizing catheter prototypes was compared to single-port catheters in infusion studies using agarose brain phantoms. Volume dispersed (V [subscript d]) and mean distribution ratios (V [subscript d] :V [subscript i]) were quantified and compared between the two catheters. The arborizing catheter produced higher V [subscript d] values; however, it did not exhibit the greatest V [subscript d] :V [subscript i], likely due to overlapping distribution volumes from the multiple individual ports. Following infusion in brain phantoms, a biotransport study of the arborizing catheter was conducted using a multiphasic finite element framework. The model was used to predict dispersion volume of a solute in a permeable hyperelastic solid matrix as a function of separation distance between adjacent ports. Results show that increasing port distance can increase V [subscript d]; however, infusion time also increases significantly with greater port distance. One way to mitigate increased infusion times is to employ higher infusion flow rates. Finally, the performance of improved arborizing catheters was compared to reflux-preventing single-port catheters in excised pig brains. CT scans were used to quantify V [subscript d] and V [subscript d] :V [subscript i] of infused iohexol (contrast-enhancing agent). The average volume dispersed for the arborizing catheter was 5.8 times greater than the single-port catheter. Mean distribution ratios for both catheters were similar. Using the multiple ports of the arborizing catheter, high V [subscript d] was achieved at a low infusion rate with negligible reflux. Given that previous attempts of CED reported poor drug distribution, the arborizing catheter may help overcome the limitations of CED.Biomedical Engineerin

Electrochemical biosensors: a nexus for precision medicine

Precision medicine is a field with huge potential for improving a patient's quality of life, wherein therapeutic drug monitoring (TDM) can provide actionable insights. More importantly, incorrect drug dose is a common contributor to medical errors. However, current TDM practice is time-consuming and expensive, and requires specialised technicians. One solution is to use electrochemical biosensors (ECBs), which are inexpensive, portable, and highly sensitive. In this review, we explore the potential for ECBs as a technology for on-demand drug monitoring, including microneedles, continuous monitoring, synthetic biorecognition elements, and multi-material electrodes. We also highlight emerging strategies to achieve continuous drug monitoring, and conclude by appraising recent developments and providing an outlook for the field

Pharma-engineering of multifunctional microneedle array device for application in chronic pain

Chronic pain poses a major concern to modern medicine and is frequently undertreated, causing suffering and disability. Transdermal delivery is the pivot to which analgesic research in drug delivery has centralized especially with the confines of needle phobias and associated pain related to traditional injections, and the existing limitations associated with oral drug delivery. Highlighted within this thesis is the possibility of further developing transdermal drug delivery for chronic pain treatment using an Electro-Modulated Hydrogel- Microneedle array (EMHM) prototype device for the delivery of analgesic medicatio

Engineering Microneedle Patches for Improved Penetration: Analysis, Skin Models and Factors Affecting Needle Insertion

Transdermal microneedle (MN) patches are a promising tool used to transport a wide variety of active compounds into the skin. To serve as a substitute for common hypodermic needles, MNs must pierce the human stratum corneum (~ 10 to 20 µm), without rupturing or bending during penetration. This ensures that the cargo is released at the predetermined place and time. Therefore, the ability of MN patches to sufficiently pierce the skin is a crucial requirement. In the current review, the pain signal and its management during application of MNs and typical hypodermic needles are presented and compared. This is followed by a discussion on mechanical analysis and skin models used for insertion tests before application to clinical practice. Factors that affect insertion (e.g., geometry, material composition and cross-linking of MNs), along with recent advancements in developed strategies (e.g., insertion responsive patches and 3D printed biomimetic MNs using two-photon lithography) to improve the skin penetration are highlighted to provide a backdrop for future research.[Figure not available: see fulltext.

Microneedles for Theranostics

Microneedle (MN) arrays were developed to provide a minimally invasive approach to detect biomarkers and deliver drugs into the ISF. Solid, hollow, and dissolvable MNs have been fabricated for various applications and have been evaluated to be very advantageous.These advantages include better patient compliance dur to painless and non-invasive administration, improved permeability and efficiency and provide targeted drug delivery by varying MN dimensions to specific regions in the skin.Techniques to fabricate MNs vary based on the material and potential application requirements. The most common techniques are micro-moulding, wet and dry etching with lithography and laser cutting. Micro-moulding fabrication have been utilized to produce various polymer, hydrogel and dissolvable MNs by filling prepared moulds with a liquid formulation. Alternatively, lithography using wet and dry etching have been used to fabricate MNs. A mask is used as a template for generating the desired pattern on a wafer surface using either a positive or negative photoresist to generate the desired pattern. These wafers are then etched using a strong caustic agent or an etcher.Finally, laser cutting techniques have been used to produce metal MN using a computer aided design to create the desired shape and dimensions.In recent studies, MNs have been created for a wide range of diagnostic and drug delivery applications. A wide range of MNs have been adapted for a variety of disease treatments such as cancer, arthritis and ophthalmic disorders. As diabetes mellitus effects approximately 30 million people and glucose monitoring has advanced from the initial self-monitoring of blood glucose levels to glucose biosensors, a high demand for MNs to be modified for diabetes management has been emphasized.This thesis details the fabrication of MNs using silicon, polyvinylpyrollidone (PVP) and polycarbonate for sensing and drug delivery. Silicon wafers with the combination of photolithography and deep-reactive ion etching (DRIE) techniques are used to create solid and hollow MNs. The MN arrays have sharp tips that provide eased insertion and injectable capabilities.Polycarbonate and PVP MNs were manufactured using micro-moulding techniques to create solid and dissolvable MNs respectively. These MNs were characterized to determine their penetration capabilities through the stratum corneum (SC) to providecontrolled transdermal drug delivery and diagnose biomarkers within the interstitial fluid (ISF).For diagnostic applications, the polycarbonate MNs were modified for glucose sensing using first generation sending strategies wherein oxygen in used as the electron acceptor and the levels of glucose is proportional to the peroxide produced. To determine drug delivery capabilities of MNs, the solid polycarbonate and silicon MNs employed ‘poke and patch’ techniques with the use of a Franz cell to show calcein and FITC-insulin delivery over 24 hours. On the other hand, for drug delivery through the dissolvable PVP MNs, ‘poke and dissolve’ techniques were analysed with the use of Franz cells to show the release of encapsulated calcein and FITC-insulin within the polymeric matrix over 24 hours. The arrays were either left blank for basal drug delivery or metallised with silver for controlled drug delivery using the metals breakdown potential

Delivering precision antimicrobial therapy through closed-loop control systems

Sub-optimal exposure to antimicrobial therapy is associated with poor patient outcomes and the development of antimicrobial resistance. Mechanisms for optimizing the concentration of a drug within the individual patient are under development. However, several barriers remain in realizing true individualization of therapy. These include problems with plasma drug sampling, availability of appropriate assays, and current mechanisms for dose adjustment. Biosensor technology offers a means of providing real-time monitoring of antimicrobials in a minimally invasive fashion. We report the potential for using microneedle biosensor technology as part of closed-loop control systems for the optimization of antimicrobial therapy in individual patients