Simulation study of the effect of molar mass dispersity on domain interfacial roughness in lamellae forming block copolymers for directed self-assembly.

A coarse-grained molecular dynamics model was used to study the thin film self-assembly and resulting pattern properties of block copolymer (BCP) systems with various molar mass dispersities. Diblock copolymers (i.e. A-b-B type) were simulated in an aligned lamellar state, which is one of the most common patterns of potential use for integrated circuit fabrication via directed self-assembly of BCPs. Effects of the molar mass dispersity (Ð) on feature pitch and interfacial roughness, which are critical lithographic parameters that have a direct impact on integrated circuit performance, were simulated. It was found that for a realistic distribution of polymer molecular weights, modeled by a Wesslau distribution, both line edge roughness (LER) and line width roughness (LWR) increase approximately linearly with increasing Ð, up to ∼45% of the monodisperse value at Р= 1.5. Mechanisms of compensation for increased A-A and B-B roughness were considered. It was found that long and short chain positions were not correlated, and that long chains were significantly deformed in shape. The increase in LWR was due to the increase in LER and a constant correlation between the line edges. Unaligned systems show a correlation between domain width and local molecular weight, while systems aligned on an alternating pattern of A and B lines did not show any correlation. When the volume fraction of individual chains was allowed to vary, similar results were found when considering the Ð of the block as opposed to the Ð of the entire system.

Transdermal delivery enhanced by antimicrobial peptides.

Magainin antimicrobial peptide has been shown to increase skin permeability by perturbing stratum corneum lipids in the skin. In this study, we hypothesized that skin permeation enhancement depends on peptide structure. We therefore measured skin permeability enhancement by modified magainin derivitives and 20 different antimicrobial peptides in a formulation containing ethanol and N-lauroyl sarcosine (NLS). We found that modification of magainin structure did not improve skin permeability enhancement. Although all six magainin-based peptides had alpha-helical structure and fluidized stratum corneum lipids, only magainin and a Gly-Ala substituted magainin with NLS and ethanol significantly increased skin permeability. Among the 20 antimicrobial peptides, only magainin itself and a Lys-Leu analog peptide showed enhancement. Overall, this is the first study to survey skin permeability enhancement by antimicrobial peptides. We conclude that over the range of conditions studied here, most antimicrobial peptides did not enhance skin permeability and that magainin peptide provided the optimal structure.

Biochemical enhancement of transdermal delivery with magainin peptide: modification of electrostatic interactions by changing pH.

Magainin is a naturally occurring, pore-forming peptide that has recently been shown to increase skin permeability. This study tested the hypothesis that electrostatic forces between magainin peptides and drugs mediate drug transport across the skin. Electrostatic interaction between positively charged magainin and a negatively charged model drug, fluorescein, was attractive at pH 7.4 and resulted in a 35-fold increase in delivery across human epidermis in vitro when formulated with 2% N-lauroylsarcosine in 50% ethanol. Increasing to pH 10 or 11 largely neutralized magainin's charge, which eliminated enhancement due to magainin. Shielding electrostatic interactions with 1-2M NaCl solution similarly eliminated enhancement. Showing the opposite dependence on pH, electrostatic interaction between magainin and a positively charged anti-nausea drug, granisetron, was largely neutralized at pH 10 and resulted in a 92-fold increase in transdermal delivery. Decreasing to pH 5 increased magainin's positive charge, which repelled granisetron and progressively decreased transdermal flux. Circular dichroism analysis, multi-photon microscopy, and FTIR spectroscopy showed no significant pH effect on magainin secondary structure, magainin deposition in stratum corneum, or stratum corneum lipid order, respectively. We conclude that magainin increases transdermal delivery by a mechanism involving electrostatic interaction between magainin peptides and drugs.

Synergistic enhancement of skin permeability by N-lauroylsarcosine and ethanol.

To develop formulations for transdermal drug delivery, this study tested the hypothesis that the anionic surfactant, N-lauroylsarcosine (NLS), and ethanol synergistically increase skin permeability by increasing the fluidity of stratum corneum lipid structure. Skin permeability experiments showed that transdermal delivery of fluorescein across human cadaver epidermis was increased by up to 47-fold using formulations containing NLS in aqueous ethanol solutions. Skin permeability was increased by increasing NLS concentration in combination with 25-50% ethanol solutions. Skin permeability was shown to correlate with skin electrical conductivity measurements, changes in differential scanning calorimetry lipid transition peak temperature, and Fourier transform infrared spectroscopy CH stretching peak shifts indicative of stratum corneum lipid fluidization and changes in protein conformation. Evidence for lipid extraction was also evident, but did not appear to be responsible for the observed increases in skin permeability. We conclude that NLS in aqueous ethanol formulations can dramatically increase skin permeability by a mechanism involving synergistic lipid-fluidization activity in the stratum corneum.

Optimization of transdermal delivery using magainin pore-forming peptide.

The skin's outer layer of stratum corneum, which is a thin tissue containing multilamellar lipid bilayers, is the main barrier to drug delivery to the skin. To increase skin permeability, our previous work has shown large enhancement of transdermal permeation using a pore-forming peptide, magainin, which was formulated with N-lauroyl sarcosine (NLS) in 50% ethanol-in-PBS. Mechanistic analysis suggested that magainin and NLS can increase skin permeability by disrupting stratum corneum lipid structure. In this study, our goal was to improve conditions that increase skin permeability by magainin by further optimizing the pretreatment time and concentration of magainin exposure. We found that skin permeability increased with increasing pretreatment time. Skin permeability also increased with increasing magainin concentration up to 1 mM, but was reduced at a magainin concentration of 2 mM. Enhancement of skin permeability to fluorescein (323 Da) up to 35-fold was observed. In contrast, this formulation did not enhance skin permeability to larger molecules, such as calcein (623 Da) and dextran (3,000 Da).

Transdermal delivery enhanced by magainin pore-forming peptide.

In this study we tested the hypothesis that magainin, a peptide known to form pores in bacterial cell membranes, can increase skin permeability by disrupting stratum corneum lipid structure. We further hypothesized that magainin's enhancement requires co-administration with a surfactant chemical enhancer to increase magainin penetration into the skin. In support of these hypotheses, exposure to a known surfactant chemical enhancer, N-lauroyl sarcosine (NLS), in 50% ethanol solution increased in vitro skin permeability to fluorescein 15 fold and the combination of magainin and NLS-ethanol synergistically increased skin permeability 47 fold. In contrast, skin permeability was unaffected by exposure to magainin without co-enhancement by NLS-ethanol. Furthermore, confocal microscopy showed that magainin in the presence of NLS-ethanol penetrated deeply and extensively into stratum corneum, whereas magainin alone penetrated poorly into the skin. Additional analysis by Fourier-transform infrared spectroscopy, X-ray diffraction, and differential scanning calorimetry showed that NLS-ethanol disrupted stratum corneum lipid structure and that the combination of magainin and NLS-ethanol disrupted stratum corneum lipids even further. Altogether, these data suggest that NLS-ethanol increased magainin penetration into stratum corneum, which further increased stratum corneum lipid disruption and skin permeability. We believe this is the first study to demonstrate the use of a pore-forming peptide to increase skin permeability. This study also presents the novel concept of using a first chemical enhancer to increase penetration of a second chemical enhancer into the skin to synergistically increase skin permeability to a model drug.

A model for the structure of MCM-41 incorporating surface roughness.

The surface area of MCM-41 mesoporous silica, estimated by several models in the literature, is significantly less than the value derived from BET analysis of nitrogen adsorption at 77.4 K. In the past, the difference has been attributed to several reasons including the errors involved in the BET analysis of the multilayer-capillary condensation region and the heterogeneity of the walls. In the present work, we present an alternate model of MCM-41 based on molecular simulations that gives surface area values that are in closer agreement to those determined by experiment. The model incorporates bulk heterogeneity of the material, surface hydroxyls, and most importantly, physical deformations or indentations of the pore surface. The model predicts small-angle X-ray diffraction (XRD) and wide-angle X-ray scattering (WAXS) results that are consistent with experimental data as well as surface areas and pore volumes that compare favorably with published experimental results. The simulation results are consistent with the hypothesis that the interstitial space in MCM-41 is relatively amorphous despite the regular arrangement of the mesopores. The surface roughness associated with the amorphous structure increases the surface area beyond the nominal value produced by assuming smooth cylindrical pores.