Drug Delivery Kinetics Research Articles

Less Is More: Antipsychotic Drug Effects Are Greater with Transient Rather Than Continuous Delivery

Most studies on the effects of antipsychotics focus on achieving threshold levels of the drug. The speed and frequency with which drug concentrations reach threshold levels and rise and fall within the day are generally ignored. Based on prior data, we predicted that variations in the within-day kinetics of antipsychotic drug delivery would produce different outcomes, even if we held achieved dose, route, and total duration of treatment constant. We compared the effects of within-day continuous (via minipump) versus transient (via subcutaneous injection) haloperidol treatment (n = 4-9/condition/experiment) at doses that yield equivalent peak levels of striatal D2 receptor occupancy (approximately 74%). Over time, transient haloperidol gained efficacy, while continuous haloperidol lost efficacy in two animal models of antipsychotic-like effects (the suppression of amphetamine-induced locomotion and conditioned avoidance responding). This was related to the fact that continuous treatment led to a greater increase in striatal D2 receptor numbers--particularly D2 receptors in a high-affinity state for dopamine--relative to transient treatment and produced behavioral dopamine supersensitivity (as indicated by an enhanced locomotor response to amphetamine following antipsychotic treatment cessation). Treatment kinetics also influenced the postsynaptic response to haloperidol. Transient treatment increased striatal c-fos messenger RNA (mRNA) expression, while continuous treatment did not. Relative to continuous antipsychotic exposure, within-day transient exposure is more efficacious behaviorally and is associated with a distinct molecular and gene expression profile. Thus, differences in the within-day kinetics of antipsychotic treatment can have different efficacy, and the potential clinical implications of this should be explored further.

Effects of Drug Hydrophobicity on Liposomal Stability

A major obstacle in drug delivery is the inability to effectively deliver drugs to their intended biological target without deleterious side-effects. Delivery vehicles such as liposomes can minimize toxic side-effects by shielding the drug from reaction with unintended targets while in systemic circulation. Liposomes have the ability to accommodate both hydrophilic and hydrophobic drugs, either in the internal aqueous core or the lipid bilayer, respectively. In the present study, fluorescein and rhodamine have been used to model hydrophilic and hydrophobic drugs, respectively. We have compared the stabilities of liposomes encapsulating these fluorophores as a function of lipid content, time, and temperature. At 25 and 37 degrees C, liposomes containing distearoyl phosphatidylcholine as the major phospholipid component were found to be more stable over time than those containing dipalmitoyl phosphatidylcholine, regardless of the fluorophore encapsulated. Liposomes loaded with fluorescein were found to be more stable than those with rhodamine. Dipalmitoyl phosphatidylcholine liposomes that encapsulated rhodamine were the least stable. The results indicate that the physical properties of the drug cargo play a role in the stability, and hence drug delivery kinetics, of liposomal delivery systems, and desired drug release times can be achieved by adjusting/fine-tuning the lipid compositions.

Mathematical models for drug delivery to chronic patients

Mathematically, analysis of drug delivery kinetics involves two moving boundary problems: diffusion front and eroding front. In this paper, we have models for drug delivery for the sites which can be enclosed by spherical shaped matrices covered by membranes and these problems are helpful for designing the drug delivery devices to deliver the drug inside from outside and a corresponding device supplying drug from inside. Once the time required for treatment and rate of drug delivery is known from medical diagnosis, this analysis can design a device releasing the drug/active agent over a long period of time. The purpose of such drug delivery is to achieve more effective therapies while eliminating the effect of over dosing and maintaining drug levels within the desired levels. The device may work on optimal use of drug and increase the patient’s convenience. The proposed models provide design for eroding tumor or chemotherapy to cancerous regions. The results have been obtained for steady state release rate, zero order release time and life time of the device and discussed. It has been observed that zero order time and life time increase by introducing a membrane of uniform thickness.

Central venous catheter infusions: A laboratory model shows large differences in drug delivery dynamics related to catheter dead volume*

Central venous catheters (CVCs) are conduits for drug infusions. Dead volumes of different CVC lumens vary considerably. This study quantitatively evaluated drug delivery dynamics of CVCs in a laboratory model of continuous drug infusion. CVCs studied included a triple-lumen catheter (16-gauge and 18-gauge lumens), the proximal infusion port of a pulmonary artery catheter, and a 9-Fr introducer sheath, with and without a pulmonary artery catheter in the lumen. One syringe pump infused a carrier. A second pump infused the model drug methylene blue (3 mL/hr), joining the carrier immediately upstream of the CVC. Samples were collected every minute for quantitative analysis. Laboratory model. None. At low fixed flow rates, experiments characterized drug delivery kinetics of different CVCs. Data collection then assessed effects of increased carrier flow. The time to steady-state delivery after initiation of methylene blue infusion differed between CVCs. At a carrier flow of 10 mL/hr, the fastest achievement of steady-state delivery was with the 18-gauge lumen of a triple-lumen catheter. The 9-Fr introducer had the slowest time to achieve steady-state delivery. Other CVCs had intermediate kinetics. Reducing drug delivery from steady state to zero after cessation of methylene blue infusion was fastest with the 18-gauge lumen and slowest with the 9-Fr introducer. Increasing carrier flow rates from 10 to 60 mL/hr hastened the time to target for initiation and cessation of methylene blue delivery. Experiments demonstrate large differences between CVCs in the dynamics for delivery of model drug methylene blue. Achieving targeted steady-state delivery, and termination of a planned continuous drug infusion, may be far slower than typically appreciated. Delivery kinetics depend on the dead volume and the rate of carrier flow. Safe and effective management of continuous drug infusions depends on understanding the dynamics of the delivery system.

Central venous catheter infusions: A laboratory model shows large differences in drug delivery dynamics related to catheter dead volume *

Objective: Central venous catheters (CVCs) are conduits for drug infusions. Dead volumes of different CVC lumens vary considerably. This study quantitatively evaluated drug delivery dynamics of CVCs in a laboratory model of continuous drug infusion. Design: CVCs studied included a triple-lumen catheter (16-gauge and 18-gauge lumens), the proximal infusion port of a pulmonary artery catheter, and a 9-Fr introducer sheath, with and without a pulmonary artery catheter in the lumen. One syringe pump infused a carrier. A second pump infused the model drug methylene blue (3 mL/hr), joining the carrier immediately upstream of the CVC. Samples were collected every minute for quantitative analysis. Setting: Laboratory model. Subjects: None. Interventions: At low fixed flow rates, experiments characterized drug delivery kinetics of different CVCs. Data collection then assessed effects of increased carrier flow. Measurement and Main Results: The time to steady-state delivery after initiation of methylene blue infusion differed between CVCs. At a carrier flow of 10 mL/hr, the fastest achievement of steady-state delivery was with the 18-gauge lumen of a triple-lumen catheter. The 9-Fr introducer had the slowest time to achieve steady-state delivery. Other CVCs had intermediate kinetics. Reducing drug delivery from steady state to zero after cessation of methylene blue infusion was fastest with the 18-gauge lumen and slowest with the 9-Fr introducer. Increasing carrier flow rates from 10 to 60 mL/hr hastened the time to target for initiation and cessation of methylene blue delivery. Conclusions: Experiments demonstrate large differences between CVCs in the dynamics for delivery of model drug methylene blue. Achieving targeted steady-state delivery, and termination of a planned continuous drug infusion, may be far slower than typically appreciated. Delivery kinetics depend on the dead volume and the rate of carrier flow. Safe and effective management of continuous drug infusions depends on understanding the dynamics of the delivery system.

Development of an aciclovir implant for the effective long-term control of herpes simplex virus type-1 infection in Vero cells and in experimentally infected SKH-1 mice

Human herpes simplex virus type-1 (HSV-1) is treatable with oral doses of an antiviral agent such as aciclovir (ACV), a drug that has poor bioavailability. An alternative for delivering ACV would employ a long-lived subcutaneous implant that would allow for near zero-order drug delivery kinetics. This study aimed to develop an implant composed of a matrix of silicone and ACV that is capable of sustained long-term release of ACV. Once the implants had been created, release of ACV from the implants was determined and quantified in vitro using a spectrophotometric assay for the drug. Solvent-exposed surface area of the implant (2.86 mm 2, 6.28 mm 2, 34.62 mm 2 and 100.48 mm 2) had a significant effect on release kinetics, whereas temperature (37 °C, 25 °C and 4 °C) and pH (6.0, 7.0 and 8.0) did not. The implants were also used successfully to suppress HSV-1 (KOS)-induced cytopathic effect in cultured Vero cells. The implants protected HSV-1-infected SKH-1 mice from viral reactivation ( n = 37; P = 0.0367) via ultraviolet light compared with mice that were untreated ( n = 37). Furthermore, mice that received silicone-only implants had no lowered risk of reactivation ( n = 34; P = 0.7268), demonstrating the antiviral efficacy of the ACV implants.

Release Kinetics of Ampicillin, Biocompatibility Tests with a Fibroblast Strain of a Zirconia Gel Glass

Biocompatibility remains the central theme for biomaterials applications in medicine. It is generally accepted that this term does not indicate only absence of a cytotoxic effect but also positive effects in the sense of biofunctionality, i.e. promotion of biological processes considering the intended aim of the application of a biomaterial. Biocompatibility of zirconia gel glass was studied using in vitro testing methods, the incubation period was 7, 14, 21 days. The bioactivity of the synthesized material had been shown by the formation of a layer of hydroxyapatite on the surface of ZrO2-Y2O3(5wt%) samples soaked in a fluid simulating the composition of the human blood plasma (SBF), as observed by SEM and EDS microscopy. Studies of drug delivery kinetics were also carried out. The amount of sodium ampicillin released has been detected by UV-VIS spectroscopy. The released kinetics seems to occur in more than one stage. HPLC analysis had also been carried out to ensure the integrity of ampicillin after the synthetic treatment. Keywords: Sol-gel, Drug delivery, In vitro biocompatibility

Surfactant–Polymer Nanoparticles Overcome P-Glycoprotein-Mediated Drug Efflux

Nanoparticles enhance the therapeutic efficacy of an encapsulated drug by increasing and sustaining the delivery of the drug inside the cell. We have previously demonstrated that Aerosol OT (AOT)-alginate nanoparticles, a novel formulation developed recently in our laboratory, significantly enhance the therapeutic efficacy of encapsulated drugs like doxorubicin in drug-sensitive tumor cells. The purpose of this study is to evaluate the drug delivery potential of AOT-alginate nanoparticles in drug-resistant cells overexpressing the drug efflux transporter, P-glycoprotein (P-gp). AOT-alginate nanoparticles were formulated using an emulsion-cross-linking process. Rhodamine 123 and doxorubicin were used as model P-gp substrates. Cytotoxicity of nanoparticle-encapsulated doxorubicin and kinetics of nanoparticle-mediated cellular drug delivery were evaluated in both drug-sensitive and -resistant cell lines. AOT-alginate nanoparticles enhanced the cytotoxicity of doxorubicin significantly in drug-resistant cells. The enhancement in cytotoxicity with nanoparticles was sustained over a period of 10 days. Uptake studies with rhodamine-loaded nanoparticles indicated that nanoparticles significantly increased the level of drug accumulation in resistant cells at nanoparticle doses higher than 200 microg/mL. Blank nanoparticles also improved rhodamine accumulation in drug-resistant cells in a dose-dependent manner. Nanoparticle-mediated enhancement in rhodamine accumulation was not because of membrane permeabilization. Fluorescence microscopy studies demonstrated that nanoparticle-encapsulated doxorubicin was predominantly localized in the perinuclear vesicles and to a lesser extent in the nucleus, whereas free doxorubicin accumulated mainly in peripheral endocytic vesicles. Inhibition of P-gp-mediated rhodamine efflux with AOT-alginate nanoparticles was confirmed in primary brain microvessel endothelial cells. In conclusion, an AOT-alginate nanoparticle system enhanced the cellular delivery and therapeutic efficacy of P-gp substrates in P-gp-overexpressing cells.

Beatmung und Analgosedierung

Every patient receiving invasive mechanical ventilation needs an adequate analgesia and sedation. Based on validated scores, the individual titration of sedation and analgesia aims to maximise patient comfort and optimise patient-ventilator synchrony. By regular re-evaluation (e. g., three times a day) of the drug doses a day-night-time rhythm, with a deeper sedation during the night, can be achieved. It is important to know that the recommendations concerning the drug doses are often based on a single application, which does not reflect the real elimination kinetics of a continuous drug delivery. This may significantly change in critically ill patients. Using a modern concept of analgo-sedation, it is often possible to establish spontaneous breathing during mechanical ventilation and to promote successful early weaning of the patient.

Influence of synthesis temperature on the structural characteristics of mesoporous silica

The characteristics of mesoporous silica prepared at different temperatures and the behavior of this system relating to the microencapsulation of a model drug were investigated. The preparation of mesoporous materials was initiated with the dissolution of a surfactant in distilled water and strong acid medium. After this, tetraethyl orthosilicate was added under agitation. The mixture was heated for 24h at the synthesis temperature (60°C, 80°C, 100°C and 130°C) under static conditions. The surfactant was removed by calcination, which was carried out by increasing the temperature to 550°C for 5h. Atenolol was used as a model drug to study the kinetics of drug delivery. It could be observed that aging materials at higher temperatures presents no microporosity, and this influences the control of the release of the model drug.

Development of a controlled release low dose class II drug-Glipizide

The purpose of this study was to develop a new monolithic matrix system to completely deliver glipizide, a Biopharmaceutics Classification System (BCS) Class II drug in a zero order manner over an extended time period. Two approaches were examined using drug in formulations that contain swellable hydroxypropylmethylcellulose (HPMC) or erodible polyethylene oxide (PEO). The matrices were prepared by dry blending selected ratios of polymers and ingredients using direct compression technique. Dissolution was assessed using modified USP apparatus II. Glucotrol XL push-pull osmotic pump (PPOP) was used as the reference. The interrelationship between matrix hydration, erosion and textural properties were determined and analyzed under the dissolution test conditions. Linear and reproducible release similar to that of Glucotrol XL was achieved for optimized matrices ( f 2 > 50) independent of hydrodynamic conditions. The kinetics of drug delivery was directly related to the synchronization of swelling, erosion and fractional release. HPMC matrices showed a significantly greater degree of hydration and swelling and stronger texture property relative to PEO matrices. Results indicate that in the case of low dose/low soluble drug, total drug release in a zero order manner heavily depends on the synchronization of erosion and swelling fronts during the entire dissolution study.

Assemblage of novel release modules for the development of adaptable drug delivery systems

The aim of this paper was to study the applicability of the release module assemblage technology for an adaptable control of drug delivery rate and site. The elementary release module was a swellable matrix having one base convex and the other concave, named Dome Matrix. The swelling and release behavior of the release module was studied. The presence of the convex and concave bases in the swellable matrix slightly changed the overall drug delivery kinetics exhibited by a flat base cylindrical matrix having the same weight and composition. The swelling and drug release of the individual bases of the matrix was also studied to investigate the effect of the surface shape. The concave, convex and flat bases exhibited different swelling and release kinetics. The convex base released drug at faster rate than the concave base, whereas the flat base was intermediate. The release mechanisms of convex and concave bases were significantly different. The Dome Matrix module was selected for assembling several modules in a delivery system obtained by a guided insertion of the convex base into the concave base or by concave/concave base sticking. The module assemblage shows different drug release behavior depending on the geometry of assembled systems.

Vascular reactions to in vivo electroporation: characterization and consequences for drug and gene delivery

In vivo electroporation (EP) is gaining momentum for drug and gene delivery. In particular, DNA transfer by EP to muscle tissue can lead to highly efficient long-term gene expression. We characterized a vascular effect of in vivo EP and its consequences for drug and gene delivery. Pulses of 10–20 000 μs and 0.1–1.6 kV/cm were applied over hind- and forelimb of mice and perfusion was examined by dye injection. The role of a sympathetically mediated vasoconstrictory reflex was investigated by pretreatment with reserpine. Expression of a transferred gene (luciferase), permeabilization (determined using 51Cr-EDTA), membrane resealing and effects on perfusion were compared to assess the significance of the vascular effects. Above the permeabilization threshold, a sympathetically mediated Raynaud-like phenomenon with perfusion delays of 1–2 min was observed. Resolution of this phase followed kinetics of membrane resealing. Above a second threshold, irreversible permeabilization led to long perfusion delays. These vascular reactions (1) affect kinetics of drug delivery, (2) predict efficient DNA transfer, which is optimal during short perfusion delays, and (3) might explain electrocardiographic ST segment depressions after defibrillation as being caused by vascular effects of EP of cardiac muscle.

CORRELATIONS BETWEEN THE RATE OF INTRACELLULAR RELEASE OF ENDOCYTOSED LIPOSOMAL DOXORUBICIN AND CYTOTOXICITY AS DETERMINED BY A NEW ASSAY

Previously, we showed that liposomes with surface-attached anti-CD19 were internalized into human B lymphoma cells through receptor-mediated endocytosis, resulting in improved anti-tumor efficacy . In order to further increase the efficacy of antineoplastic drug-containing liposomes, we have taken advantage of this internalization process by producing triggered release liposomes that rapidly release drug from the enzyme-rich, acidic environment of lysosomes. To analyze the effectiveness of these triggered-release formulations, we developed a nuclear accumulation assay for doxorubicin (DXR) that allows us to determine the rate of cytoplasmic drug delivery subsequent to drug release from the endosomal/lysosomal compartments by examining the rate of accumulation of drug in cellular nuclei. We demonstrate the usefulness of this assay by comparing the kinetics of cytoplasmic drug delivery for DXR-containing, pH-sensitive, triggered release liposomes versus DXR-containing, non-sensitive, liposomal formulations. We see a significant correlation between the rate of nuclear accumulation of DXR and its in vitrocytotoxicity. This indicates that pH-sensitive formulations traffic drug to the cytoplasm and the nucleus significantly more rapidly than do non-sensitive formulations. We conclude that the development of triggered release liposomes is a promising strategy for further improving the therapeutic efficacy of liposomal antineoplastic drugs targeted selectively to cancer cells by surface-attached ligands that bind to internalizing epitopes.

Modeling of the drug delivery from a hydrophilic transdermal therapeutic system across polymer membrane

A mathematical simulation is presented which describes the in vitro drug delivery kinetics from hydrophilic adhesive water-soluble poly- N-vinylpyrrolidone (PVP) –polyethylene glycol (PEG) matrices of transdermal therapeutic systems (TTS) across skin-imitating hydrophobic Carbosil membranes. Propranolol is employed as the test drug. The contributions of the following physicochemical determinants to drug delivery rate control have been estimated: the drug diffusion coefficients both in the matrix and the membrane; the membrane - matrix drug partition coefficient: the drug concentration in the matrix and the membrane thickness. Drug transfer from the hydrophilic matrix across the membrane is shown to be controlled by the drug partitioning from the matrix into the membrane. The best correlation between simulation data and experimental results is obtained when the effect of membrane hydration is taken into consideration during in vitro drug release.

Analytical Light Microscopy: Examples of Practical Problemsolving and Efficiency in Pharmaceutical Quality Control and Formulation

Five applications of analytical light microscopy to problem-solving in the pharmaceutical industry are described and illustrated by case examples. Problems included are (1) the caking of pharmaceutical products, (2) chemical incompatibility, (3) nucleation and precipitation, (4) recognition of hydrates and polymorphs, and (5) identification and sourcing of contaminant particles.Considerable effort goes into the sizing of solid pharmaceutical raw materials and products. In many instances, particle size is used to help control the rate and uniformity of dissolution, which in turn affects the kinetics of drug delivery. Caking is a macroscopic description of the change in a sample from a finely-divided powder to a single solid molded aggregate. Caking obviously has a severe impact on handling and dissolution characteristics.Caking of a powder is almost always caused by moisture through the cyclical dissolution and precipitation on the surfaces of the particles. When exposed to sufficient vapor pressure, often through changes in humidity or temperature,

Modeling of percutaneous drug transport in vitro using skin-imitating Carbosil membrane

A comparative study of the barrier function of human skin and polydimethylsiloxane–polycarbonate block copolymer Carbosil membrane was performed in vitro using 14 drugs spanning a wide range of structures and therapeutic classes. The drug permeability coefficients across the skin and the Carbosil membrane were examined as an explicit dependence of permeant molecular weight, melting point, solubility in aqueous solution and octanol–water partition coefficient. Owing to heterophase and heteropolar structure, Carbosil membranes and human skin epidermis share a common solubility–diffusion mechanism of drug transport. This synthetic membrane is shown to provide a mechanistically substantiated model for percutaneous drug absorption. Carbosil membranes can be used both for quantitative prediction of transdermal drug delivery rate and as a skin-imitating standard membrane in the course of in vitro drug delivery kinetics evaluation.

Polymer‐drug conjugates: Manipulation of drug delivery kinetics

AbstractThree methods of manipulating the kinetics of hydrolysis of polymer conjugates were evaluated. It was demonstrated that either first‐order, zero‐order or S‐shaped kinetic profiles could be achieved by systematic changes in the chemical composition of several series of model side‐chain substituted polyacrylates. The changes in kinetics were shown to arise from an increase in the rate constant during solvolysis, resulting from predictable changes in either the water content, secondary structure, or LCST of the polymer conjugate.

Polymer-drug conjugates: manipulating drug delivery kinetics using model LCST systems

Model studies of the kinetics of hydrolysis of side chain substituted polymers exhibiting a lower critical solution temperature (LCST) were undertaken. Copolymers of N-isopropyl acrylamide (NiPAm) and N-acryloxy succinimide (AS) were prepared by radical polymerization of the monomers or by reaction of isopropylamine with poly( N-acryloxy succinimide). The LCSTs of the copolymers were measured by DSC and shown to depend on both the NiPAm/AS ratio and the copolymer microstructure. The kinetics of hydrolysis of the succinimide side chain were measured at temperatures below, at, and above the LCST of the copolymers. The LCST increased on conversion of the acryloxy succinimide groups to acrylic acid groups during the hydrolysis process. At temperatures below the LCST, the polymers were water soluble throughout the hydrolysis and exhibited first order kinetics. Above the LCST, the polymers were initially insoluble but became soluble as hydrolysis caused a progressive increase in the LCST. The rate of hydrolysis accelerated on dissolution. As a result, the kinetics exhibited either a zero order or an S-shaped profile. In the latter case the initial slow phase was dependent on the difference between the reaction temperature and the initial LCST.

Correlation of the intravenous in-line drug delivery kinetics with the diluent flow rate, angle of internal flow, wettability, solubility and particle surface area

The primary objectives of this work were to investigate various parameters that would potentially affect the delivery kinetics of drugs via an in-line intravenous (IV) delivery system and to establish a mathematical model to correlate the drug delivery kinetics with these parameters. The in-line delivery system contains a drug containing device which is placed between a parenteral solution (which is also termed as the diluent) container and a patient. The solid drug in the device is automatically dissolved by the diluent and administered to the patient as the diluent solution flows through the system via an administration set at a controlled flow rate. This system comprises numerous advantages over the conventional infusion systems, including labor-saving, convenient to use and minimizing human error. The delivery kinetics of this system was assessed using T Net95 which is defined as the time to deliver 95% of drug, excluding the lag time, via this system. The values of T Net95 for various drugs were experimentally determined in this study. A semi-empirical regression equation was used to fit the experimental data. In this equation, T Net95 is expressed in terms of the five parameters, the diluent flow rate (FR), angle of internal flow Θ, contact angle θ, solubility C s , and the particle surface area (SA). The regression analysis was performed using the statistical package (SAS) and the results indicated that the most important parameters affecting T Net95 are FR, Θ and θ for the drugs investigated. A close fit of the regression equation to the experimental data was observed, with R 2 equal to 0.99. The resulting equation is expressed as T Net95 = − 60.88 + 1980.7/FR + 330.88/Θ 1 2 + 15.34/ cos θ . Using this equation, the delivery kinetics of other drugs in this in-line system may be predicted, provided that the angle of internal flow Θ and the contact angle θ of the drugs are available or determined. In order to give a close prediction, the solubility of the drug of interest should be similar to the range of solubility investigated in this paper.