Microneedle-Based Intradermal Delivery Enables Rapid Lymphatic Uptake and Distribution of Protein Drugs

Purpose  

The purpose of this research was to examine the pharmacokinetics (PK) of drug uptake for microneedle-based intradermal (ID) delivery of several classes of protein drugs compared to standard subcutaneous (SC) administration.     

Identification of Peptide Ligands for Targeting to the Blood-Brain Barrier

Purpose  

Transport of drugs to the brain is limited by the blood-brain barrier. New, specific brain endothelium ligands can facilitate brain-specific delivery of drugs.     

Activation of Antigen-Specific T Cell-Responses by Mannan-Decorated PLGA Nanoparticles

Purpose  

Mannosylation of vaccines is a promising strategy to selectively target vaccine antigens to the mannose receptor expressed on dendritic cells (DCs). The purpose of this study was to investigate the effect of mannan (MN) chemically conjugated to poly(D, L-lactide-co-glycolic acid) (PLGA) nanoparticles (NPs) on antigen-specific T-cell responses elicited by a model antigen (ovalbumin, OVA) loaded in PLGA-NPs.     

Hydrogel-Forming Microneedles Increase in Volume During Swelling in Skin,but Skin Barrier Function Recovery is Unaffected

We describe, for the first time, quantification of in-skin swelling and fluid uptake by hydrogel-forming microneedle (MN) arrays and skin barrier recovery in human volunteers. Such MN arrays, prepared from aqueous blends of hydrolyzed poly(methylvinylether/maleic anhydride) (15%, w/w) and the cross-linker poly(ethyleneglycol) 10,000 Da (7.5%, w/w), were inserted into the skin of human volunteers (n = 15) to depths of approximately 300 μm by gentle hand pressure. The MN arrays swelled in skin, taking up skin interstitial fluid, such that their mass had increased by approximately 30% after 6 h in skin. Importantly, however, skin barrier function recovered within 24 h after MN removal, regardless of how long the MN had been in skin or how much their volume had increased with swelling. Further research on closure of MN-induced micropores is required because transepidermal water loss measurements suggested micropore closure, whereas optical coherence tomography indicated that MN-induced micropores had not closed over, even 24 h after MN had been removed. There were no complaints of skin reactions, adverse events, or strong views against MN use by any of the volunteers. Only some minor erythema was noted after patch removal, although this always resolved within 48 h, and no adverse events were present on follow-up. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association.     

Efficiency of Fatty Acids as Chemical Penetration Enhancers: Mechanisms and Structure Enhancement Relationship

Purpose  

The present study evaluated the effects of fatty acids commonly present in cosmetic and topical formulations on permeation enhancement across human epidermal membrane (HEM) lipoidal pathway when the fatty acids saturated the SC lipid domain without cosolvents (Emax).     

Microneedle Pre-treatment of Human Skin Improves 5-Aminolevulininc Acid (ALA)- and 5-Aminolevulinic Acid Methyl Ester (MAL)-Induced PpIX Production for Topical Photodynamic Therapy Without Increase in Pain or Erythema

Purpose  

To determine the impact of skin pretreatment with microneedles (MNs) on ALA- and MAL-induced protoporphyrin IX (PpIX) production, as well as MN impact on pain sensations during light exposure and erythema after PDT.     

Blood−brain barrier transporters and response to CNS-active drugs

Background  

The capillary endothelial cells of the blood−brain barrier express an array of uptake and efflux drug transporters. Regulated expression and function of these transporters govern the central nervous system (CNS) penetration of essential nutrients, therapeutic drugs and, in some cases, toxins. Emerging evidence supports the notion of interplay between uptake and efflux drug transport as the determinants that define the extent of exposure of many drugs and their CNS action.     

Review of patents on microneedle applicators

Transdermal drug delivery offers certain advantages over conventional oral or parenteral administration. However, transdermal delivery is not available to many promising therapeutic agents, especially high molecular weight hydrophilic compounds. This is due to the excellent barrier property of the superficial skin layer, the stratum corneum (SC). Only drugs with very specific physicochemical properties (molecular weight < 500 Da, adequate lipophilicity, and low melting point) can be successfully administered transdermally. Of the several active approaches used to enhance the transport of drugs through the SC, the use of microneedles (MNs) has recently been shown to be very promising and has attracted considerable attention by researchers from both industry and academia. MNs, when used to puncture skin, will by-pass the SC and create transient aqueous transport pathways of micron dimensions and enhance the transdermal permeability. However, for effective performance of these MNs in drug delivery applications, irrespective of the type, material, height and density, it is imperative that they penetrate into the skin with the greatest possible accuracy and reproducibility. Due to the inherent elasticity and irregular surface topography of the skin, it remains a major challenge to the reproducibility of MN penetration. Therefore, in order to achieve uniform and reproducible MN penetration into skin, an external source of assistance could be very useful. Accordingly, this review deals with various innovative applicator designs developed by industry and research centres in the context of effective application of MN arrays for transdermal drug delivery, as disclosed in the recent patent literature.     

Lipophilicity and Transporter Influence on Blood-Retinal Barrier Permeability: A Comparison with Blood-Brain Barrier Permeability

Purpose  

To determine the lipophilicity trend line from the relationship between the blood-retinal barrier (BRB) permeability and the lipophilicity of permeants and compare it with that of the blood-brain barrier (BBB).     

Physicochemical Selectivity of the BBB Microenvironment Governing Passive Diffusion—Matching with a Porcine Brain Lipid Extract Artificial Membrane Permeability Model

Purpose  

To mimic the physicochemical selectivity of the blood-brain barrier (BBB) and to predict its passive permeability using a PAMPA model based on porcine brain lipid extract (PBLE 10%w/v in alkane).     

Reverse Iontophoresis of Amino Acids: Identification and Separation of Stratum Corneum and Subdermal Sources <Emphasis Type="BoldItalic">In Vitro</Emphasis>

Purpose  

To differentiate the stratum corneum (SC) and subdermal sources of amino acids (AAs) extracted by reverse iontophoresis.     

Development of a Smart Nano-vehicle to Target Cerebrovascular Amyloid Deposits and Brain Parenchymal Plaques Observed in Alzheimer’s Disease and Cerebral Amyloid Angiopathy

Purpose  

To design a smart nano-vehicle (SNV) capable of permeating the blood-brain barrier (BBB) to target cerebrovascular amyloid formed in both Alzheimer’s disease (AD) and cerebrovascular amyloid angiopathy (CAA).     

Novel Imaging Method to Quantify Stratum Corneum in Dermatopharmacokinetic Studies: Proof-of-Concept with Acyclovir Formulations

Purpose

Tape-stripping the stratum corneum (SC) is used in the assessment of dermatopharmacokinetics (DPK). The amount of SC per tape can be determined gravimetrically, but a novel imaging method offers advantages in terms of sensitivity, reproducibility, precision, stability and speed. High-resolution images, acquired under controlled conditions, are analysed in terms of pixel greyscale values and distributions, and their usefulness in DPK studies is demonstrated in this study using acyclovir.

Methods

At all tape-stripped sites, the SC amount per tape was measured gravimetrically and by imaging. In a first series of experiments, untreated sites were stripped to determine total SC thickness. Subsequently, post-application of two acyclovir creams, drug-permeation profiles were constructed.

Results

The greyscale values from the imaging data can be used directly to estimate total SC thickness and DPK parameters. The results compared favourably with the traditional weighing method. The concentration of drug on each tape, as a function of the relative position within the SC, permitted diffusivity and partitioning parameters characterising the penetration of acyclovir to be derived.

Conclusion

The new imaging approach offers a sensitive, reproducible, precise, and rapid technique to quantify the relative SC amount removed on tape-strips, and facilitates the acquisition of DPK data.     

Antiepileptic drug use in community-dwelling and institutionalized elderly: a nationwide study of over 1 300 000 older people

Purpose  

To investigate whether institutionalization is associated with the use of antiepileptic drugs (AEDs) and to compare the association between use of AEDs and psychotropics in community-dwelling and institutionalized elderly, after adjustment for age, sex and co-morbidity (i.e. number of other drugs).     

Exacerbation of inflammatory bowel diseases associated with the use of nonsteroidal anti-inflammatory drugs: myth or reality?

Background  

Nonsteroidal anti-inflammatory drugs (NSAIDs), conventional and selective cyclooxygenase-2 (COX-2) inhibitors, are among the most widely used medications for the treatment of various inflammatory conditions. There is strong evidence of a possible association between the use of these drugs and the relapse of inflammatory bowel diseases (IBD).     

Multifunctional Peptide-PEG Intercalating Conjugates: Programmatic of Gene Delivery to the Blood-Brain Barrier

Purpose  

To enhance transfection efficacy of pDNA through the application of multifunctional peptide-PEG-tris-acridine conjugates (pPAC) and the formation of biodegradable core-shell polyplexes for gene delivery to the blood-brain barrier (BBB).     

Effect of metronidazole on the pharmacokinetics of fexofenadine,a P-glycoprotein substrate,in healthy male volunteers

Objective  

Metronidazole has been reported to cause various drug interactions when co-administered with certain drugs. One possible mechanism for this action is through an inhibition of P-glycoprotein (P-gp). We have assessed the possible inhibitory effects of metronidazole on P-gp-mediated drug disposition in healthy subjects using fexofenadine as a P-gp substrate.     

Drug clearance during Continuous Veno-Venous Hemofiltration (CVVH). A mathematical model based on ex-vivo experiments

Introduction:

Continuous veno-venous hemofiltration (CVVH) with an AN69 membrane is used in hemodynamical unstable patients with acute renal failure admitted to the Intensive Care Unit (ICU) of the Catharina Hospital in Eindhoven (CHE), the Netherlands. Literature search revealed that only the clearance and kinetics of some antibiotics during CVVH were studied. Data obtained with different renal replacement techniques and membranes can’t easily be extrapolated to CVVH with an AN69 membrane. (Reetze-Bonorden et al., 1993; Mueller et al., 2003) Due to the lack of clinical research data, dosages in patients treated with CVVH at the ICU of the CHE or are not adjusted or are adjusted on the base of the empirical determined creatinin clearance of 30 ml/min. For aminoglycosides and vancomycin dose adjustment is performed applying therapeutic drug monitoring. Because of this a lot of drugs are possibly suboptimal dosed during CVVH.

Aim:

The aim of this study was to develop a predictive mathematical model based on ex-vivo experiments for the drug clearance by CVVH with an AN69 high-flux membrane.

Methods:

The experimental set-up consisted of a PRISMA CFM hemofiltration machine with a AN69 HF 0,9 m², 500 ml heparinised bovine blood as blood compartment, blood flow rate 150 ml/min and ultrafiltration rate 1500 ml/h. The following drugs were added to the blood compartment in therapeutic concentrations, covering a broad range in molecular weight (Mw), % protein binding (%PB), logP and charge (C): amiodarone, amitriptyline, carbamazepine, cyclosporine, clozapine, digoxin, phenobarbital, phenytoin, gentamycin, midazolam, acetaminophen, theophylline, tobramycin, valproic acid and vancomycin. The sieving coefficient (SC) was calculated by SC=(2x concentration ultrafiltrate) / (concentration post membrane + concentration pre membrane).

Results:

All four parameters; %PB, logP, C and Mw contributed statistically significant (p < 0,05) to the SC. The regression line, explaining 75% of the variance (R²=0,751) is:

Conclusion:

Based on the ex-vivo experiments a mathematical model has been extracted to predict a-priori the sieving coefficient of drugs during CVVH with an AN69 high-flux membrane on the base of protein binding, charge, logP and molecular weight. This model has to be validated in vivo and can then be used, if valid, for drugs which physico-chemical properties in the ranges studied: p%PB 0 − 98%, logP −7,32 – 7, Mw 151 – 1500, C −1 – 3.     

In vitro-in vivo extrapolation of zolpidem as a perpetrator of metabolic interactions involving CYP3A

Objectives  

To evaluate zolpidem as a mechanism-based inactivator of human CYP3A in vitro, and to assess its metabolic interaction potential with CYP3A drugs (in vitro-in vivo extrapolation; IV-IVE).