Preparation and Evaluation of Diltiazem Hydrochloride Diffusion-Controlled Transdermal Delivery System

The objective was to investigate the suitable polymeric films for the development of diltiazem hydrochloride (diltiazem HCl) transdermal drug delivery systems. Hydroxypropyl methylcellulose (HPMC) and ethylcellulose (EC) were used as hydrophilic and hydrophobic film formers, respectively. Effects of HPMC/EC ratios and plasticizers on mechanical properties of free films were studied. Effects of HPMC/EC ratios on moisture uptake, in vitro release and permeation through pig ear skin of diltiazem HCl films were evaluated. Influence of enhancers including isopropyl myristate (IPM), isopropyl palmitate (IPP), N-methyl-2-pyrrolidone, oleic acid, polyethylene glycol 400, propylene glycol, and Tween80 on permeation was evaluated. It was found that addition of EC into HPMC film produced lower ultimate tensile strength, percent elongation at break and Young’s modulus, however, addition of EC up to 60% resulted in too hard film. Plasticization with dibutyl phthalate (DBP) produced higher strength but lower elongation as compared to triethyl citrate. The moisture uptake and initial release rates (0–1 h) of diltiazem HCl films decreased with increasing the EC ratio. Diltiazem HCl films (10:0, 8:2 and 6:4 HPMC/EC) were studied for permeation because of the higher release rate. The 10:0 and 8:2 HPMC/EC films showed the comparable permeation-time profiles, and had higher flux values and shorter lag time as compared to 6:4 HPMC/EC film. Addition of IPM, IPP or Tween80 could enhance the fluxes for approx. three times while Tween80 also shorten the lag time. In conclusion, the film composed of 8:2 HPMC/EC, 30% DBP and 10% IPM, IPP or Tween80 loaded with 25% diltiazem HCl should be selected for manufacturing transdermal patch by using a suitable adhesive layer and backing membrane. Further in vitro permeation and in vivo performance studies are required.     

Molecular Dynamics Simulation of a Micellar System

We present the results of an atomistic molecular dynamics simulation based on the AMBER/OPLS force field applied to segments of isolated one-dimensional micelles, 2,3,6,7,10,11-Hexa-(1,4,7-Trioxaoctyl)-Triphenylene, in aqueous solution using the SPC/E water model. The quantities which we study include the intra-micellar monomer structure, e.g., the equilibrium monomer-monomer separation along the micelle, the micelle-water interface, which yields the effective micellar diameter, and the flexibility of the micelle in terms of its persistence length as a function of temperature. In addition, we determine the micelle size distribution at low concentration via the free enthalpy gain per monomer-monomer contact using a hydration shell model in combination with thermodynamic integration. Finally, we locate the isotropic-to-nematic transition by using our results as input for an analytical model.     

Transdermal Delivery of a Tetrapeptide: Evaluation of Passive Diffusion

Skin penetration of the tetrapeptide Ac-Ala-Ala-Pro-Val-NH₂ was assessed. This peptide sequence fits the P-P₁ subsites of elastase and inhibits human neutrophil elastase competitively. Consequently this peptide may be therapeutically useful in a variety of inflammatory disorders, including psoriasis, in which elevated levels of human neutrophil elastase have been reported. Peptide penetration was assessed across whole human skin, whole skin with the stratum corneum removed by tape stripping and epidermis, which had been removed from the dermis by heat separation. The influence of 75 aqueous ethanol as a potential penetration enhancer of the tetrapeptide across epidermis was also assessed. The tetrapeptide did not penetrate whole human skin or epidermis, even under the influence of 75 aqueous ethanol. However, when the stratum corneum was removed tetrapeptide flux of 73.39 μg cm² h⁻¹ was achieved. The study demonstrates that the stratum corneum is the main barrier to tetrapeptide skin penetration and must be overcome if therapeutically relevant amounts of tetrapeptide are to be delivered to the skin.     

分子动力学模拟与分子生物力学

生物大分子的微观结构动力学决定其生物学功能,其力学-化学耦合规律是分子生物力学的重点关注方向。分子动力学模拟是耦合生物大分子力学-化学性质微观结构动力学基础的有效手段,其结果可用于预测结构-功能关系、指导实验设计和诠释实验结果。本文简要介绍了分子动力学模拟的方法学特点、基本工作原理及其在分子生物力学中的应用,并展望了未来可能的发展方向和应用前景。     

Transdermal Delivery of Proteins

Transdermal delivery of peptides and proteins avoids the disadvantages associated with the invasive parenteral route of administration and other alternative routes such as the pulmonary and nasal routes. Since proteins have a large size and are hydrophilic in nature, they cannot permeate passively across the skin due to the stratum corneum which allows the transport of only small lipophilic drug molecules. Enhancement techniques such as chemical enhancers, iontophoresis, microneedles, electroporation, sonophoresis, thermal ablation, laser ablation, radiofrequency ablation and noninvasive jet injectors aid in the delivery of proteins by overcoming the skin barrier in different ways. In this review, these enhancement techniques that can enable the transdermal delivery of proteins are discussed, including a discussion of mechanisms, sterility requirements, and commercial development of products. Combination of enhancement techniques may result in a synergistic effect allowing increased protein delivery and these are also discussed.     

Evaluation of Meloxicam-Loaded Cationic Transfersomes as Transdermal Drug Delivery Carriers

The aim of this study is to develop meloxicam (MX)-loaded cationic transfersomes as skin delivery carriers and to investigate the influence of formulation factors such as cholesterol and cationic surfactants on the physicochemical properties of transfersomes (i.e., particle size, size distribution, droplet surface charge and morphology), entrapment efficiency, stability of formulations and in vitro skin permeation of MX. The transfersomes displayed a spherical structure. Their size, charge, and entrapment efficiency depended on the composition of cholesterol and cationic surfactants in the formulation. Transfersomes provided greater MX skin permeation than conventional liposomes and MX suspensions. The penetration-enhancing mechanism of skin permeation by the vesicles prepared in this study may be due to the vesicle adsorption to and/or fusion with the stratum corneum. Our results suggest that cationic transfersomes may be promising dermal delivery carriers of MX.     

Molecular Dynamics Simulation on a Parallel Computer

For the purpose of molecular dynamics simulations of large biopolymers we have built a parallel computer with a systolic loop architecture, based on Transputers as computational units, and have programmed it in occam II. The computational nodes of the computer are linked together in a systolic ring. The program based on this topology for large biopolymers increases its computational throughput nearly linearly with the number of computational nodes. The program developed is closely related to the simulation programs CHARMM and XPLOR, the input files required (force field, protein structure file, coordinates) and output files generated (sets of atomic coordinates representing dynamic trajectories and energies) are compatible with the corresponding files of these programs. Benchmark results of simulations of biopolymers comprising 66, 568, 3 634, 5 797 and 12 637 atoms are compared with XPLOR simulations on conventional computers (Cray, Convex, Vax). These results demonstrate that the software and hardware developed provide extremely cost effective biopolymer simulations. We present also a simulation (equilibrium of X-ray structure) of the complete photosynthetic reaction center of Rhodopseudomonas viridis (12 637 atoms). The simulation accounts for the Coulomb forces exactly, i.e. no cut-off had been assumed.     

Molecular Dynamics Simulation of Linear Polymers in a Solvent

This paper reports a series of simulations of a single linear polymer chain in solution. Both the monomer units and the solvent particles are represented by “beads” which interact via a purely repulsive shifted Lennard-Jones potential; the chains themselves are constructed by linking beads with relatively stiff elastic bonds. The chain lenghts range from 8 to 48 beads, and the total system size is between 1000 and 14000 beads. The static and dynamic properties of the polymer chains obtained from long simulations of these systems (over 10⁶ timesteps) are discussed, and the size and density dependence of the chain behavior examined.     

Molecular Dynamics Simulation of Nucleation and Growth of a Binary Quasicrystal

Abstract

The quasicrystal structure is considered to be a new type of ordered phase because its Fourier transform has Laue spots with icosahedral symmetry, which is inconsistent with crystal structure. Computer simulation of the formation process of a quasicrystal was performed by the molecular dynamics method. On the basis of the Strandburg type of quasicrystal model, we developed an algorithm of the formation process of binary quasicrystal reflecting the procedure as realistically as possible. The Fourier transform of some of the obtained structures has shown decagonal symmetry although the spots are rather diffused. It has been shown that the potential parameter and experimental condition should be limited to produce a perfect quasicrystal structure.     

Elastic Vesicles as a Tool for Dermal and Transdermal Delivery

The main problem in delivery of drugs across the skin is the barrier function of the skin, which is located in the outermost layer of the skin, the stratum corneum. The stratum corneum consists of corneocytes surrounded by lipid layers, the so-called lipid lamellae. When applying drugs onto the skin, the major penetration pathway is the tortuous intercellular route along the lipid lamellae. In order to increase the number of drugs administered via the transdermal route, novel drug delivery systems have to be designed. Among these systems are iontophoresis, electroporation, microneedles, and vesicular systems.     

The Effect of Nanoemulsion as a Carrier of Hydrophilic Compound for Transdermal Delivery

The purpose of the present study was to investigate the effect of nanoemulsions as a carrier vehicle of hydrophilic drug for transdermal delivery. The response surface methodology with a mixture design was used to evaluate the effect of ingredient levels of nanoemulsion formulations including cosurfactant (isopropyl alcohol, 20∼30%), surfactant (mixed of Brij 30 and Brij 35, 20∼30%), and distilled-water (34.5∼50.0%) on properties of the drug-loaded nanoemulsions including physicochemical characters and drug permeability through rat skin. The result showed that the hydrophilic drug in aqueous solution with or without penetration enhancer could not transport across rat skin after 12 h of application. Used nanoemulsions as carrier vehicle, the permeation rate of drug was significantly increased from 0 to 63.23 µg/cm²/h and the lag time was shortened from more than 12 h to about 2.7∼4.0 h. Moreover, the drug-loaded nanoemulsion formulation also showed physicochemical stability after 3 month storage at 25°C and 40°C.     

Molecular Dynamics Simulation of Hexamine and Suberic Acid

In order to perform a molecular dynamics (MD) simulation of the incommensurate crystalline structure hexamethylenetetramine suberate (C 6 H 12 N 4 )(HOOC-(CH 2 ) 6 -COOH), we present in a first step the separate simulations of the crystalline structure of each of the two pure components, hexamethylenetetramine (HMT) and suberic acid. The domain decomposition parallel MD program ddgmq is used for this purpose. A second-generation consistent force field (CFF91) is employed to describe the interactions between atoms. Starting from experimental crystal structures, both pure components were heated from low to high temperatures. Our MD results show that the HMT system can be well represented by CFF91. In the case of suberic acid the layered structure of the crystal is largely preserved although deviations in the unit cell lengths from the experimental values are ～10%. Rather than attempt a complex re-parametrisation of CFF91 we chose to impose a fixed compensating external pressure tensor to correct for the deficiencies of the chosen force field. After optimising this compensating external pressure tensor at one temperature we find that experimental lattice constants and angles can be well reproduced over a range of temperatures.     

Computer Simulation by Molecular Dynamics as a Tool for Modelling of Molecular Systems

Abstract

A survey is given of methods for simulation of molecular systems on a computer. The various assumptions, approximations and limitations are discussed and the possibility of making comparisons with experimental quantities is assessed. Finally, a number of practical applications of molecular dynamics simulation techniques in chemistry are reviewed.     

Effect of Adhesive Layer Thickness and Drug Loading on Estradiol Crystallization in a Transdermal Drug Delivery System

The effects of adhesive layer thickness and drug loading on estradiol crystallization were studied in a drug-in-adhesive patch. Patches containing different estradiol loadings (1.1% and 1.6% w/w) in different thicknesses (45, 60, and 90 μm) were prepared by coating of a homogenous mixture of adhesive solution and the drug on a siliconized release liner by a film applicator. After drying, the film was laminated on a Poly(ethylene terephthalate) backing layer and cut into appropriate size. Release tests were performed using thermostated Chien-type diffusion cells. Cross-section of the patches was observed by optical microscopy. Scanning electron microscopy was done for surface analysis of the patches after drug release test. Crystal formation was not expected in the adhesive layer based on the linear free-energy relationship formalisms however; crystalline regions were observed in different locations through the thickness of the patches. These regions were significantly more discontinuous in 45 μm samples which elucidated the effective role of adhesive layer thickness in drug crystallization. Extensive crystallization observed for thicker patches was attributed to the strong crosslinking capability of estradiol hemihydrate. Drug release study confirmed some of the crystallization results. No significant increase was observed in the burst release with increasing in thickness from 45 to 60 μm which can be attributed to the severe increase in the crystallization extent. Also, formation of a crystalline layer near the releasing surface and more discontinuous pattern of the crystals in some samples was confirmed by investigation of the drug release curves.     

Investigating Transdermal Delivery of Vitamin D3

Transdermal delivery of therapeutic amounts of vitamin D₃ is proposed to overcome its variable oral bioavailability, especially for people who suffer from fat malabsorption. The main challenge for this delivery route is to overcome the barrier properties of skin, especially for very lipophilic compounds such as vitamin D₃. In this study, the effect of different penetration enhancers, such as oleic acid, dodecylamine, ethanol, oleic acid in propylene glycol, isopropyl myristate, octyldodecanol, and oleyl alcohol in propylene glycol were evaluated in vitro for their effectiveness in delivering vitamin D₃ through polyamide filter, polydimethylsiloxane membrane, and porcine skin. A diffusion cell was used to study the transdermal permeability of vitamin D₃. Ointment formulations of vitamin D₃ were prepared containing the most widely used penetration enhancers, oleic acid, and dodecylamine. The ointment containing oleic acid as chemical penetration enhancer did not improve delivery compared to control. On the other hand, the formulation containing dodecylamine as a penetration enhancer did improve the transdermal delivery of vitamin D₃. However, statistical significance and an amount high enough for nutritional supplementation purposes were reached only when the skin was pretreated with 50% ethanol. In these conditions, the ointment delivered an amount of 760-ng vitamin D₃ per cm² of skin. The research shows promise that transdermal delivery could be an effective administration route for vitamin D₃ when ethanol and dodecylamine are used as penetration enhancers.KEY WORDS: dodecylamine, ethanol, penetration enhancer, transdermal delivery, vitamin D₃     

Studies on Transdermal Delivery Enhancement of Zidovudine

The purpose of this study was to investigate physicochemical characteristics and in vitro release of zidovudine from monolithic film of Eudragit RL 100 and ethyl cellulose. Films included 2.5% or 5% (w/w) zidovudine of the dry polymer weight were prepared in various ratios of polymers by solvent evaporation method from methanol/acetone solvent mixture. The release studies were carried out by vertical Franz cells (2.2 cm² area, 20 ml receptor fluid). Ex vivo studies were done on Wistar rat skin within the films F6 (Eudragit RL100) and F7 (Eudragit RL100/Ethylcellulose, 1:1) consisting 5% (w/w) zidovudine in comparison with the same amount of free drug. Either iontophoresis (0.1 and 0.5 mA/cm² direct currents, Ag/AgCl electrodes) or dimethyl sulfoxide (pretreatment of 1% and 5%, w/w, solutions) were used as enhancers. Films consisting of ethyl cellulose under the ratio of 50% (w/w) gave similar release profiles, and the highest in vitro cumulative released amount was achieved with F6 film which gave the closest results with the free drug. This result could be due to the high swelling capacity and re-crystallization inhibition effect of RL 100 polymer which also influenced the film homogenization. All the films were fitted to Higuchi release kinetics. It was also observed that both 0.5-mA/cm² current and 5% (w/w) dimethyl sulfoxide applications significantly increased the cumulative permeated amount of zidovudine after 8 h; however, the flux enhancement ratio was higher for 0.5-mA/cm² current application, especially within F6 film. Thus, it was concluded that Eudragit RL100 film (F6) could be further evaluated for the transdermal application of zidovudine.     

Mechanical Properties of a Complete Microtubule Revealed through Molecular Dynamics Simulation

Microtubules (MTs) are the largest type of cellular filament, essential in processes ranging from mitosis and meiosis to flagellar motility. Many of the processes depend critically on the mechanical properties of the MT, but the elastic moduli, notably the Young's modulus, are not directly revealed in experiment, which instead measures either flexural rigidity or response to radial deformation. Molecular dynamics (MD) is a method that allows the mechanical properties of single biomolecules to be investigated through computation. Typically, MD requires an atomic resolution structure of the molecule, which is unavailable for many systems, including MTs. By combining structural information from cryo-electron microscopy and electron crystallography, we have constructed an all-atom model of a complete MT and used MD to determine its mechanical properties. The simulations revealed nonlinear axial stress-strain behavior featuring a pronounced softening under extension, a possible plastic deformation transition under radial compression, and a distinct asymmetry in response to the two senses of twist. This work demonstrates the possibility of combining different levels of structural information to produce all-atom models suitable for quantitative MD simulations, which extends the range of systems amenable to the MD method and should enable exciting advances in our microscopic knowledge of biology.     

Molecular Dynamics Simulation on the Connection Machine

An algorithm for the efficient calculation of macromolecular force fields on the Connection Machine is described. The full force field is separated into bond interactions and non-bonding interactions. Only the latter are implemented on the Connection Machine, the former, less computationally intensive tasks are performed by an existing, conventional molecular dynamics code on the front end. Parallelization of the evaluation of non-bonding interactions is achieved by the Replicated Systolic Loop algorithm introduced in this paper. The algorithm is a variant of the Systolic Loop scheme often used for the computation of 2-particle forces for the classical N-particle problem.