Drug Delivery Kinetics Research Articles

The suprachoroidal space as a route of administration to the posterior segment of the eye.

The suprachoroidal space (SCS) is a potential space between the sclera and choroid that traverses the circumference of the posterior segment of the eye. The SCS is an attractive site for drug delivery because it targets the choroid, retinal pigment epithelium, and retina with high bioavailability, while maintaining low levels elsewhere in the eye. Indeed, phase III clinical trials are investigating the safety and efficacy of SCS drug delivery. Here, we review the anatomy and physiology of the SCS; methods to access the SCS; kinetics of SCS drug delivery; strategies to target within the SCS; current and potential clinical indications; and the safety and efficacy of this approach in preclinical animal studies and clinical trials.

Three-Month Randomized Clinical Trial of Nasal Calcitonin in Adults with X-linked Hypophosphatemia.

Previous work has demonstrated that a single subcutaneous dose of salmon calcitonin leads to a transient decline in circulating levels of FGF23 in patients with X-linked hypophosphatemia (XLH). Since the calcitonin receptor is expressed on osteocytes, this raises the possibility that interdicting signals through that receptor could modulate circulating levels of FGF23 in XLH. In the present study, 21 subjects with XLH were randomly assigned to receive either placebo nasal spray or 400IU of nasal salmon calcitonin daily for three months. On the first and last day of the study, serial measurements of FGF23, 1,25-dihydroxyvitamin D, and TmP/GFR were made over 27h. At the beginning of Visit 2 (the first day of month 2) and the beginning of Visit 3 (the first day of month 3), single, first-morning, fasting measurements of these same parameters were made before the next administered dose of study drug. Following the initial or final dose of study drug, there were no differences in area under the curve, based on treatment assignment, for the three principal outcome variables. Similarly, there were no differences in the fasting measures taken at the beginning of Visit 2 or Visit 3 compared to the fasting values on either day 2 of Visit 1 or the fasting values on day 2 of Visit 4. There were also no significant changes over time in serum phosphorus, serum calcium, circulating levels of PTH, CTx, or P1NP. The reasons why nasal salmon calcitonin did not recapitulate the findings with subcutaneously administered drug may relate to the kinetics of drug delivery, the bioavailability of drug or peak drug dose achieved. It remains possible, however, that other means of altering calcitonin receptor signaling may still provide an opportunity for regulating FGF23 production.

Time-of-flight secondary ion mass spectrometry analyses of vancomycin.

As an antibiotic that prevents and treats infections caused by Gram-positive bacteria such as Staphylococcus aureus, vancomycin incorporated in a biodegradable polymer poly(lactide-co-glycolide) provides opportunities to construct controlled-release drug delivery systems. Developments associated with this promising system have been largely concentrated on areas of drug delivery kinetics and biodegradability. In order to provide surface analytical approaches to this important system, the authors demonstrate applicability of time-of-flight secondary ion mass spectrometry (TOF-SIMS) in three-dimensional molecular imaging for a model system consisting of alternating layers of ploy(lactide-co-glycolide) and vancomycin. TOF-SIMS imaging clarified that the two chemicals can undergo phase separation when dimethyl sulfoxide is used as the solvent. The authors identified two diagnostic ions that are abundant and structural moieties of vancomycin. The results on TOF-SIMS imaging and depth profiling vancomycin provide useful information for further applications of TOF-SIMS in the development of antibiotic drug delivery systems involving the use of vancomycin.

Development and evaluation of an isolated limb infusion model for investigation of drug delivery kinetics to solid tumors by thermosensitive liposomes and hyperthermia

The combined administration of thermosensitive liposomes (TSLs) and hyperthermia (HT) has been increasingly shown to be a powerful tool for the treatment of solid tumors. At present, it is hypothesized that the circulation of TSLs through the vasculature of a heated tumor results in the rapid release of the entrapped drug, followed by its uptake and distribution within the tumor microenvironment. However, simple questions on the transport kinetics of TSLs through the heated tumor and how much drug is retained upon passage of TSLs through the tumor microcirculation have not been investigated in an experimental setting to-date. The present work describes a novel methodology for investigating these parameters by isolated limb infusion (ILI), developed in a rat model of sarcoma. This approach was used to assess the efficacy of Doxorubicin (Dox) delivery by TSL in a heated (42°C) tumor following a single passage of TSL through the tumor vasculature. Analysis of the effluent post-ILI, whole-tumor histological sections, and tissue homogenates revealed that upon a single passage, Dox delivery by TSL at 42°C did not exceed delivery under conventional (i.e. free Dox) or physiological (i.e. TSL at 37°C, or normothermia; NT) conditions. In fact, mathematical modeling demonstrated that at least thirteen passages are required to obtain the intratumoral Dox levels typically achieved using TSL (i.e. ~5%ID/g). Overall, this work investigates TSL-based determinants for achieving efficacious drug delivery using a model of ILI in tumor-bearing rats and the results bear important implications for TSL disposition in vivo.

Fabrication of chitosan-g-poly(acrylamide)/CuS nanocomposite for controlled drug delivery and antibacterial activity

In present study, we reported the synthesis of chitosan-g-poly(acrylamide)/CuS (CPA/CS) nanocomposite for controlled delivery of ofloxacin. The CPA/CS nanocomposites were characterized by Fourier transmission infrared spectroscopy (FTIR), UV–visible spectroscopy (UV), scanning electron microscopy (SEM), X-ray diffraction (XRD) analysis. From the FTIR spectra, the various groups present in CPA/CS nanocomposite were monitored. The homogeneity, morphology and crystallinity of the CPA/CS nanocomposite were ascertained from SEM/EDX and XRD data, respectively. The kinetics of ofloxacin drug delivery was investigated at different pH. The drug released studies were investigated at different pH (2.2, 7.4 and 9.4) and time intervals (2, 4, 6, 8, 10, 12, 14, 16h). The drug release behavior depends upon the pH of medium and the nature of matrix. The maximum drug loading efficiency of 85% was recorded for CPA/CS. The maximum drug release of 76% was observed at 2.2. pH after 18h onto CPA/CS. Nanocomposites were also tested for antibacterial activity against Escherichia coli bacteria. About 97% killing of E. coli was observed after 24h.

Fabrication of electrospun nanofibres of BCS II drug for enhanced dissolution and permeation across skin

The present work reports preparation of irbesartan (IBS) loaded nanofibre mats using electrospinning technique. The prepared nanofibres were characterized by scanning electron microscopy, Fourier transform infrared spectroscopy, differential scanning calorimetry, X-ray diffraction analysis, in vitro diffusion and ex vivo skin permeation studies. FTIR studies revealed chemical compatibility of IBS and polyvinyl pyrrolidine (PVP K-30). SEM images confirmed formation of nanofibres wherein IBS existed in amorphous form as revealed by DSC and XRD analyses. The prepared nanofibre mats of IBS were found to be superior to IBS loaded as cast films when analysed for in vitro IBS release and ex vivo skin permeation studies since the flux of IBS loaded nanofibres was 17 times greater than as cast film. The improvement in drug delivery kinetics of IBS loaded nanofibres could be attributed to amorphization with reduction in particle size of IBS, dispersion of IBS at molecular level in PVP matrix and enormous increase in the surface area for IBS release due to nanonization. Thus transdermal patch of IBS loaded nanofibres can be considered as an alternative dosage form in order to improve its biopharmaceutical properties and enhance therapeutic efficacy in hypertension.

HPMA-based block copolymers promote differential drug delivery kinetics for hydrophobic and amphiphilic molecules

We describe a method how polymeric nanoparticles stabilized with (2-hydroxypropyl)methacrylamide (HPMA)-based block copolymers are used as drug delivery systems for a fast release of hydrophobic and a controlled release of an amphiphilic molecule. The versatile method of the miniemulsion solvent-evaporation technique was used to prepare polystyrene (PS) as well as poly-d/l-lactide (PDLLA) nanoparticles. Covalently bound or physically adsorbed fluorescent dyes labeled the particles’ core and their block copolymer corona. Confocal laser scanning microscopy (CLSM) in combination with flow cytometry measurements were applied to demonstrate the burst release of a fluorescent hydrophobic drug model without the necessity of nanoparticle uptake. In addition, CLSM studies and quantitative calculations using the image processing program Volocity® show the intracellular detachment of the amphiphilic block copolymer from the particles’ core after uptake. Our findings offer the possibility to combine the advantages of a fast release for hydrophobic and a controlled release for an amphiphilic molecule therefore pointing to the possibility to a ‘multi-step and multi-site’ targeting by one nanocarrier. Statement of SignificanceWe describe thoroughly how different components of a nanocarrier end up in cells. This enables different cargos of a nanocarrier having a consecutive release and delivery of distinct components. Most interestingly we demonstrate individual kinetics of distinct components of such a system: first the release of a fluorescent hydrophobic drug model at contact with the cell membrane without the necessity of nanoparticle uptake. Secondly, the intracellular detachment of the amphiphilic block copolymer from the particles’ core after uptake occurs. This offers the possibility to combine the advantages of a fast release for a hydrophobic substance at the time of interaction of the nanoparticle with the cell surface and a controlled release for an amphiphilic molecule later on therefore pointing to the possibility to a ‘multi-step and multisite’ targeting by one nanocarrier. We therefore feel that this could be used for many cellular systems where the combined and orchestrated delivery of components is prerequisite in order to obtain the highest efficiency.

A poly(ether-ester) copolymer for the preparation of nanocarriers with improved degradation and drug delivery kinetics

This paper reports the synthesis and the physicochemical, functional and biological characterisations of nanocarriers made of a novel di-block biodegradable poly(ether-ester) copolymer. This material presents tunable, fast biodegradation rates, but its products are less acidic than those of other biosorbable polymers like PLGA, thus presenting a better biocompatibility profile and the possibility to carry pH-sensitive payloads. A method for the production of monodisperse and spherical nanoparticles is proposed; drug delivery kinetics and blood protein adsorption were measured to evaluate the functional properties of these nanoparticles as drug carriers. The copolymer was labelled with a fluorescent dye for internalisation tests, and rhodamine B was used as a model cargo to study transport and release inside cultured cells. Biological tests demonstrated good cytocompatibility, significant cell internalisation and the possibility to vehiculate non-cell penetrating moieties into endothelial cells. Taken together, these results support the potential use of this nanoparticulate system for systemic administration of drugs.

In vitro bioactivity and drug release kinetics studies of mesoporous silica-biopolymer composites

Targeted drug delivery systems become highly significant in certain diseases where the required dosage of drug cannot be delivered due to poor blood circulation in the targeted hard tissues. The present study reports a simple method of preparing mesoporous silica (SBA-15)/Biopolymer composite and loading an antibiotic in the silica scaffold which may find applications in bone drug delivery system. The SBA-15 was prepared under different conditions and analyzed for its texture and structural properties. The as prepared silica was characterized by low angle X-ray diffraction and BET surface area measurement which shows mesoporosity associated with hexagonally organized channels, a narrow pore size distribution and a large surface area. Chitin and Chitosan were the biopolymers used in the preparation of composites and bioactivity of the composites was investigated in the SBF medium. Ciprofloxacin was used as a model drug molecule in the drug delivery studies as its molecular size is suitable for inclusion within the mesopores of the SBA-15 material. The in vitro drug release was investigated in the simulated body fluid medium. The mesoporous silica’s were found to be highly bioactive and found to possess sustained drug delivery kinetics.

Controlling drug delivery kinetics from mesoporous titania thin films by pore size and surface energy.

The osseointegration capacity of bone-anchoring implants can be improved by the use of drugs that are administrated by an inbuilt drug delivery system. However, to attain superior control of drug delivery and to have the ability to administer drugs of varying size, including proteins, further material development of drug carriers is needed. Mesoporous materials have shown great potential in drug delivery applications to provide and maintain a drug concentration within the therapeutic window for the desired period of time. Moreover, drug delivery from coatings consisting of mesoporous titania has shown to be promising to improve healing of bone-anchoring implants. Here we report on how the delivery of an osteoporosis drug, alendronate, can be controlled by altering pore size and surface energy of mesoporous titania thin films. The pore size was varied from 3.4 nm to 7.2 nm by the use of different structure-directing templates and addition of a swelling agent. The surface energy was also altered by grafting dimethylsilane to the pore walls. The drug uptake and release profiles were monitored in situ using quartz crystal microbalance with dissipation (QCM-D) and it was shown that both pore size and surface energy had a profound effect on both the adsorption and release kinetics of alendronate. The QCM-D data provided evidence that the drug delivery from mesoporous titania films is controlled by a binding–diffusion mechanism. The yielded knowledge of release kinetics is crucial in order to improve the in vivo tissue response associated to therapeutic treatments.

Breaking the skin barrier: achievements and future directions.

Skin delivery is more advantageous for drug administration than other routes since it is more compliant and can avoid the first-pass metabolic effect. More importantly, it can ensure stable blood level of transdermal drugs for a long period of time, avoiding fluctuation and reducing side effects. However, it is restricted by the barrier function of the stratum corneum. Therefore, significant attention has been paid to developing methods to modify the kinetics of skin drug delivery and expand the range of drugs that can be used for transdermal delivery. Novel mechanisms of increasing the intercellular and appendages penetration pathways have also been developed. This review focuses on chemical penetration enhancers, physical permeabilization (sonophoresis, iontophoresis and microneedles) and novel nanocarriers for skin delivery. Recent developments on skin delivery are also discussed.

Interactions in aromatic probe molecule loaded poly(N-isopropylacrylamide) hydrogels and implications for drug delivery

Small aromatic molecules are known to interact with poly(N-isopropylacrylamide) (PNIPA) based hydrogels, one of the most frequently employed polymers in temperature induced drug delivery systems. These interactions are poorly understood at the molecular level. In this article we investigate PNIPA both at the macroscopic and at the molecular level using measurements of swelling, differential scanning microcalorimetry (DSC), X-ray powder diffraction (XRD) and solid state 1H NMR methods. The nature and the strength of the interactions affect the efficiency and kinetics of drug delivery. Phenols exert a major influence on PNIPA by reducing its phase transition temperature. The effect depends linearly on the phenol concentration, and is influenced also by the number of phenolic OH groups, as well as their relative positions. The strong interaction between phenol and the polymer that is detected by NMR hinders the crystallisation of phenol when the water is gradually evaporated. The aminoethyl phenol derivative dopamine has a much more limited effect, but in the opposite direction – the transition temperature increases slightly. The strong interaction observed among the dopamine molecules disables the polymer–dopamine interaction and favours crystallization of the dopamine when water is removed. These results reveal that embedding the drugs into polymer matrices for controlled delivery can alter the crystallinity of the stored molecules. As morphology is one of the crucial factors in delivery, this may compromise the rate and the efficiency of release.

Kinetics of Ultrasonic Drug Delivery from Targeted Micelles.

To minimize the adverse side effects of conventional chemotherapy, a targeted micellar drug carrier was investigated that retains hydrophobic drugs in its core and then releases the drug via ultrasonic activation. This paper compares the percent drug release from folated versus non-folated micelles by insonation at 70 kHz and different acoustic power densities. The encapsulated drug is Doxoru- bicin (Dox). A physical model of zero-order release with first-order re-encapsulation was used to fit the experimental kinetic data. Additionally, the acoustic activation power density and Gibbs free energy were introduced and calculated for folated and non-targeted micelles. The data suggests an important role of inertial cavitation in drug release and the presence of a power density threshold for inertial cavitation.

Probe-inspired nano-prodrug with dual-color fluorogenic property reveals spatiotemporal drug release in living cells.

The versatility of the fluorescent probes inspires us to design fluorescently traceable prodrugs, which enables tracking the drug delivery kinetics in living cells. Herein, we constructed a self-indicating nanoprodrug with two fluorescent moieties, an aggregation-induced emission molecule (tetraphenylethylene, TPE) and a luminant anticancer drug (doxorubicin, DOX), with a pH-responsive linker between them. Except when a low pH environment is encountered, an energy-transfer relay (ETR) occurs and inactivates the fluorescence of both, showing a dark background. Otherwise, the ETR would be interrupted and evoke a dual-color fluorogenic process, giving distinct fluorogenic read out. By observing the dual-color fluorogenic scenario, we captured the kinetics of the drug release process in living cells. Because the separated TPE and DOX are both fluorescent but have a distinct spectrum, by examining the spatiotemporal pattern of TPE and DOX, we were able to precisely disclose the drug-releasing site, the releasing time, the destinations of the carriers, and the executing site of the drugs at subcellular level. Furthermore, different intracellular drug release kinetics between free doxorubicin and its nanoformulations were also observed in a real-time manner.

Interaction and release kinetics study of hybrid polymer blend nanoparticles for pH independent controlled release of an anti-viral drug

Incompatible interactions of polymers with active chemical entity offer variable challenges in drug delivery kinetics. This study focuses on development of hybrid polymer blend nanoparticles with amphiphilic (Poly Vinyl Pyrrolidone) and hydrophobic (Ethyl cellulose and Eudragit RSPO) polymers to encapsulate maximum drug without significant incompatibility. Optimized nanoparticles developed using Acyclovir model drug exhibited 80% entrapment with size and surface charge of 100 nm and +26 mV, respectively. Spherical morphology and solid state transition of drug from crystalline to amorphous in nanoparticles was confirmed by SEM and XRD analysis. pH independent in-vitro drug release was observed in four different media with initial burst release followed by sustained release for >12 h. Statistically significant difference (P < 0.05) was observed in percentage of drug release from each formulation in different media. H-bonding and hydrophobic interactions between drug and polymer (FTIR, TG-DTA analysis and Makoid–Banakar Kinetics) and diffusion of drug from matrix nanospheres followed by pore transport were the key factors for effective drug release kinetics. Uptake of nanoparticles by corneal epithelial cells was more prominent within 30 min, however viability of cells was not altered significantly. Release kinetics and interactions studies revealed the suitability of polymer blend nanoparticles for better encapsulation and sustained release of the drug.

Abstract 17459: Drug Eluting Balloon Angioplasty is a Safe Treatment Option for In-stent Restenosis: Meta-analysis of Current Evidence

Introduction: Drug eluting balloons (DEB) were recently approved by FDA for peripheral artery interventions only. For coronary in-stent restenosis (ISR), the ACC/AHA/SCAI 2011 PCI guidelines have no recommendations on role for DEB. While ESC/EACTS 2010 PCI guidelines, have level IIa recommendation for DEB for ISR after a bare metal stent. The drug delivery kinetics with DEB allows shorter duration of dual anti-platelet therapy and has a potential role in ballooning side branches of a bifurcating lesion after stenting. Aim: To compare safety and efficacy of DEB angioplasty vs. plain old balloon angioplasty (BA) or drug eluting stent (DES) for treating coronary ISR. Methods and Results: A thorough search was performed on Pubmed, Embace and Google scholar databases for randomized control trials (RCT) comparing DEB vs. BA or DES for ISR. We compared target lesion revascularization (TLR) and MACE events for these groups. We also pooled data from registries and observation studies on DEB for outcome analysis. Total number of patients with DEB’s in our study was 3465, with 693 DEB’s in 8 RCT’s. Mean follow up period was 11 months. Pooled analysis showed significant benefit for DEB compared to plain old BA, for events of target lesion revascularization (OR= 0.25, p&lt;0.0001), and death (OR=0.31, p&lt;0.0001). Comparing DEB to DES, there was no statistical difference in outcomes comparing TLR (OR=1.4, p=0.14), MI or death (OR=0.65, p=0.39). Cumulative incidence of target lesion revascularization (TLR) with DEB was 6.7%. Conclusions: For coronary ISR, drug eluting balloon angioplasty is superior to plain old balloon angioplasty in terms of safety and outcomes. However, comparing drug eluting balloons vs. drug eluting stents in ISR, the outcomes are comparable and will need larger studies powered to make definitive recommendation.

Illustrative neonatal cases regarding drug delivery issues.

Illustrative neonatal cases regarding drug delivery issues.

3-dimensional (3D) fabricated polymer based drug delivery systems.

Drug delivery from 3-dimensional (3D) structures is a rapidly growing area of research. It is essential to achieve structures wherein drug stability is ensured, the drug loading capacity is appropriate and the desired controlled release profile can be attained. Attention must also be paid to the development of appropriate fabrication machinery that allows 3D drug delivery systems (DDS) to be produced in a simple, reliable and reproducible manner. The range of fabrication methods currently being used to form 3D DDSs include electrospinning (solution and melt), wet-spinning and printing (3-dimensional). The use of these techniques enables production of DDSs from the macro-scale down to the nano-scale. This article reviews progress in these fabrication techniques to form DDSs that possess desirable drug delivery kinetics for a wide range of applications.

Controlled release delivery of penciclovir via a silicone (MED-4750) polymer: kinetics of drug delivery and efficacy in preventing primary feline herpesvirus infection in culture

BackgroundHerpesviruses are ubiquitous pathogens that infect and cause recurrent disease in multiple animal species. Feline herpesvirus-1 (FHV-1), a member of the alphaherpesvirus family, causes respiratory illness and conjunctivitis, and approximately 80% of domestic cats are latently infected. Oral administration of famciclovir or topical application of cidofovir has been shown in masked, placebo-controlled prospective trials to reduce clinical signs and viral shedding in experimentally inoculated cats. However, to the authors’ knowledge, other drugs have not been similarly assessed or were not safe or effective. Likewise, to our knowledge, no drugs have been assessed in a placebo-controlled manner in cats with recrudescent herpetic disease. Controlled-release devices would permit long-term administration of these drugs and enhance compliance.MethodsWe therefore engineered implantable cylindrical devices made from silicone (MED-4750) impregnated with penciclovir, for long-term, steady-state delivery of this drug.ResultsOur data show that these devices release penciclovir with a burst of drug delivery until the tenth day of release, then at an average rate of 5.063 ± 1.704 μg per day through the next 50 days with near zero-order kinetics (in comparison to MED-4750-acyclovir devices, which show the same burst kinetics and average 2.236 ± 0.625 μg/day thereafter). Furthermore, these devices suppress primary infection of FHV-1 in a cell culture system.ConclusionsThe clinical deployment of these silicone-penciclovir devices may allow long-term treatment of FHV-1 infection with a single intervention that could last the life of the host cat.

A HumanIn VitroModel That Mimics the Renal Proximal Tubule

Human in vitro-manufactured tissue and organ models can serve as powerful enabling tools for the exploration of fundamental questions regarding cell, matrix, and developmental biology in addition to the study of drug delivery dynamics and kinetics. To date, the development of a human model of the renal proximal tubule (PT) has been hindered by the lack of an appropriate cell source and scaffolds that allow epithelial monolayer formation and maintenance. Using extracellular matrices or matrix proteins, an in vivo-mimicking environment can be created that allows epithelial cells to exhibit their typical phenotype and functionality. Here, we describe an in vitro-engineered PT model. We isolated highly proliferative cells from cadaveric human kidneys (human kidney-derived cells [hKDCs]), which express markers that are associated with renal progenitor cells. Seeded on small intestinal submucosa (SIS), hKDCs formed a confluent monolayer and displayed the typical phenotype of PT epithelial cells. PT markers, including N-cadherin, were detected throughout the hKDC culture on the SIS, whereas markers of later tubule segments were weak (E-cadherin) or not (aquaporin-2) expressed. Basement membrane and microvilli formation demonstrated a strong polarization. We conclude that the combination of hKDCs and SIS is a suitable cell-scaffold composite to mimic the human PT in vitro.