Peptide Washout and Permeability from Glyceryl Monooleate Buccal Delivery Systems

ABSTRACT

Simultaneous evaluation of the permeation and washout of a peptide from the mucoadhesive liquid crystalline phases of glyceryl monooleate (GMO) has been investigated using a donor compartment flow-through diffusion cell. [d-Ala², d-Leu⁵]enkephalin (DADLE) was incorporated into the cubic and lamellar liquid crystalline phases of GMO and applied to excised porcine buccal mucosa mounted in the donor compartment flow-through cell. Phosphate-buffered saline pH 7.4 (PBS) was pumped across the upper surface of the liquid crystalline phases to mimic salivary flow. The steady-state fluxes of DADLE and GMO from the cubic phase were significantly greater than that from the lamellar phase (P<0.01). There was no statistical difference between the amounts of DADLE and GMO washed out from the lamellar and cubic phases (P>0.05). The donor compartment flow-through diffusion cell was found to be a useful tool to evaluate the impact of salivary washout on mucoadhesive oral mucosal delivery systems.     

Simulation of water permeability and water vapor diffusion through hardened cement paste

The transport properties of cement-based materials significantly affect their durability. This results from the fact that most of the damaging reagents are transported, often solved in water, through the open pore space into the microstructure. This paper focuses on simulating water permeation (movement under a gradient of pressure) and water vapor diffusion (movement under a gradient of concentration) through hardened cement paste (hcp). The main goal is to derive the water permeability and the water vapor diffusion coefficient directly from the morphology of the 3D microstructure. For this purpose microtomographic images of a hcp made of ordinary Portland cement are used to represent the microstructure and especially the pore space through which the moisture transport will occur. With the use of a skeletonization algorithm, also known as “thinning algorithm”, the skeleton or centerline of the pore space is extracted. This skeleton is in a second step converted into a transportation network of cylindrical tubes. Bernoulli's law is applied to every tube for simulating water permeation. The permeability coefficient is then calculated by using Darcy's law. In the case of water vapor diffusion the diffusion coefficient is calculated using Fick's law. An erratum to this article is available at .     

Systemic enhancement of papaverine transdermal gel for erectile dysfunction

To enhance the systemic transdermal delivery of papaverine for the treatment of erectile dysfunction, several factors that influence transdermal delivery of papaverine HCl were studied. The effects of membrane types for in vitro permeation study, human skin layers, solvent/cosolvent systems and the penetration enhancers on the transdermal permeation of papaverine HCl were investigated. A combination of caproic acid, ethanol and water in the volume ratio of 50%:30%:20% was chosen as penetration enhancer and incorporated in two gel bases: 18% Pluronic F-127 and 2% Carbopol 940. In vivo skin permeation studies were performed with two loading doses (0.6% and 2%) in rabbits. The flux and permeability coefficient of papaverine HCl through different human skin layers suggested that the major barrier layer for papaverine HCl was residing primarily in the stratum corneum. However, the viable epidermis and dermis layer also contributed certain degrees of diffusion resistance. Differential Scanning Calorimetry study showed that penetration enhancer exhibited a counter effect with papaverine HCl on the temperature and enthalpy in both gels. In vitro drug release study demonstrated significant increases in the steady-state flux, permeability coefficient and enhancement ratio in these gels. Faster drug transports and higher bioavailability were also observed in rabbits. Skin irritation test performed in rabbits demonstrated a mild skin reaction with mean PII scores of 2 and below; however the recovery was fast. In conclusion, caproic acid, ethanol and water in the volume ratio of 50%:30%:20% is an effective penetration enhancer to deliver papaverine HCl transdermally for systemic absorption.     

Wasserpermeation durch Polymere und keramische Substrate

Water permeation through polymers and oxide layers For the measurement of water permeation through solid materials plates (TorrSeal (epoxy resin) and FIMO (composite of PVC and calk)) and Polycarbonate foils – at different ambient temperatures – a device consisting of three parts, one filled with water, the second holds the material to be measured and the last contains a capacity humidity sensor, was used. Permeation of liquid water and water vapour was tested with no difference in results. The sensitivity for the measurement of the water permeation and the diffusion coefficient was 7,98 · 10^?13 m²/s. For polycarbonate foils the diffusion coefficient, its temperature dependence and its activation energy were found to be in reasonable agreement with data from literature. In later experiments the materials will be coated with different barrier layers to further decrease permeation.     

Cellulosic solid films exhibiting cholesteric liquid crystalline order

Ethyl cellulose (EC) and hydroxypropyl cellulose (HPC) films were cast under different conditions and were observed optically. The creep behaviour of those films was determinedin vacuo as a function of applied stress or temperature and was analysed on the basis of the Eyring thermally activated process.EC and HPC films cast from liquid crystal-forming systems remained cholesteric liquid crystalline order (the cholesteric sense was different in each case), whereas EC film cast from non-liquid crystal system (benzene) had no liquid crystalline order and was amorphous. The Eyring activated process could be applied to the creep behaviour of our films and activated parameters could be evaluated. The activated volumeV was of the order of 1 nm³ and greatly depended on the casting conditions and testing temperature. The value ofV tended to decrease as the liquid crystalline order increased. The value ofV was smaller than the size of liquid crystalline domain.     

Drug release from lipid liquid crystalline phases: relation with phase behavior

Introduction: We studied the release of propranolol hydrochloride (PHCl), a water-soluble amphiphilic drug, from monoolein (MO)/water and phytantriol/water systems. Methods: We related the dissolution profiles with phase behavior and viscosity of the different liquid crystalline phases. Diolein has been added aiming to stabilize the cubic phases and thus preventing formation of less viscous (lamellar) phases. Results: Formulations display first-order release rates and diffusion release mechanism. Some formulations (mostly MO) were close to zero-order release in the first 120 minutes. Discussion: Release mechanism can be influenced by phase changes during dissolution. Conclusions: Both MO and phytantriol show good potential to be used for propranolol hydrochloride sustained drug release.     

Modeling of the mechanical behavior of composite at different relative humidities

The moisture diffusion and mechanical response in shear of a laminate constituted of 12 layers of glass fabric fiber/epoxy resin were evaluated. The experimental analysis of the moisture absorption of the specimens conditioned at different relative humidities, 0, 60, and 96% RH at 60°C was to determine the two parameters characteristic of the Fick diffusion law (the diffusion coefficient D and the maximum quantity of water of saturation M _m ) which admits the reversibility of the phenomenon. The analysis of the mechanical response in shear of the specimens oriented at 45° tested in uniaxial tension at constant imposed displacement rates, has permitted to show that the influence of the moisture concentration for the composite is very important at 96% RH. The proposed simple model makes it possible to specify the influence of water absorption on the mechanical behavior in shear. Translated from Problemy Prochnosti, No. 4, pp. 133–140, July–August, 2009.     

The effect of formation of the liquid crystalline phase on the blood compatibility of a cholesterol modified silicone

Cholesterol modified silicones were synthesized by grafting copolymerization of 10-Cholesteryloxydecanol onto polymethylhydrosiloxane (PMHS). Fourier transform infrared (FT-IR) spectroscopy, proton nuclear magnetic resonance (¹H-NMR) spectroscopy and gel permeation chromatography (GPC) confirmed the chemical structures of polymers. Differential scanning calorimetry (DSC) and polarized optical microscopy (POM) results indicated the mesogenic properties of those polymers. The modified silicone with 45% 10-Cholesteryloxydecanyl (SC45) indicated obvious thermotropic liquid crystalline transform at about 122–124.9C. The thermotropic liquid crystalline phase could be retained at room temperature via a special annealing/quenching process. The anneal-quenched film (SC45C) formed continuous liquid crystalline phase, whereas the unannealed films presented amorphous structure. The blood compatibility of the coatings was assessed from SEM observation of the platelets adhesion to coating surface and plasma recalcification time (PRT). The results revealed that the formation of the liquid crystalline phase could greatly improve the in vitro blood compatibility of the materials. The positive results of liquid crystalline onto haemocompatibility allow broad potential in biomaterials.     

Modeling of Moisture Diffusion in Heterogeneous Epoxy Resin Containing Multiple Randomly Distributed Particles Using Hybrid Moisture Element Method

This paper employs a novel numerical technique, designated as the hybrid moisture element method (HMEM), to model and analyze moisture diffusion in a heterogeneous epoxy resin containing multiple randomly distributed particles. The HMEM scheme is based on a hybrid moisture element (HME), whose properties are determined by equivalent moisture capacitance and conductance matrixes calculated using the conventional finite element formulation. A coupled HME-FE scheme is developed and implemented using the commercial FEM software ABAQUS. The HME-FE scheme is then employed to analyze the moisture diffusion characteristics of a heterogeneous epoxy resin layer containing particle inclusions. The analysis commences by comparing the performance of the proposed scheme with that of the conventional FEM in modeling the moisture diffusion process. Having validated its performance, the scheme is then employed to investigate the relationship between the volume fraction of the particles in the resin composite and the rate of moisture diffusion. It is found that moisture diffusion is retarded significantly as the volume fraction of particles increases.
The HMEM approach proposed in this study provides a straightforward and efficient means of modeling moisture diffusion in a heterogeneous epoxy resin containing multiple randomly distributed particles since only one HME moisture characteristic matrixes needs to be calculated for all HMEs sharing the same characteristics. Furthermore, different volume fractions can be modeled without modifying the original model simply by controlling the size of the inter-phase region within the HME domain.     

Long-Term Skin Permeation Kinetics of Estradiol (I): Effect of Drug Solubilizer-Polyethylene Glycol 400

Abstract

A skin permeation cell was recently developed to overcome the deficiencies noted in the currently available in vitro diffusion cells, and to provide a cell design which is suitable for studying the long-term drug permeation kinetics through the skin and is also sensitive enough for assessing the mechanisms of skin permeation by a high performance liquid chromatography.

To evaluate the rote of drug reservoir concentration in the kinetics of skin permeation as well as to maintain a sink condition in the receptor solution, the water-miscible polyethylene glycol (PEG) 400 was incorporated into the saline solution to act as a solubilizer to enhance the aqueous solubility of the relative water-insoluble estradiol. The equilibrium solubility of estradiol at 37°C was observed to in crease exponentially as increasing the volume fraction of PEG 400 added.

The rates o f permeation of estradiol across the male and female hairless mouse, whole and stripped skins excised freshly from the abdominal region, were measured a t various PEG concentrations and the permeability coefficients were determined. The permeability co-efficients were found t o decrease as increasing the PEG concentration. A linear relationship was established between th e permeability co-efficients and the skin /solution partition coefficients and the steady-stated if fusivity was calculated. Effect of sex was assessed.

The rate of permeation and the permeability coefficient across the stratum corneum were determined, using t h e multi-laminated dif-fusional resistance model. Results demonstrated that the stratum corneum acts as the rate-limiting barrier in the skin permeation of estradiol and the incorporation of upto 40% v/v PEG 400 does not in-fluence the barrier propertiesof stratum corneum, even though PEG 400 has been found to affect the aqueous solubility, permeability co-efficient, and skin /solution partition coefficient of estradiol.     

Development of novel amisulpride-loaded liquid self-nanoemulsifying drug delivery systems via dual tackling of its solubility and intestinal permeability

Objective: The aim of the current investigation was at enhancing the oral biopharmaceutical behavior; solubility and intestinal permeability of amisulpride (AMS) via development of liquid self-nanoemulsifying drug delivery systems (L-SNEDDS) containing bioenhancing excipients.

Methods: The components of L-SNEDDS were identified via solubility studies and emulsification efficiency tests, and ternary phase diagrams were constructed to identify the efficient self-emulsification regions. The formulated systems were assessed for their thermodynamic stability, globule size, self-emulsification time, optical clarity and in vitro drug release. Ex vivo evaluation using non-everted gut sac technique was adopted for uncovering the permeability enhancing effect of the formulated systems.

Results: The optimum formulations were composed of different ratios of Capryol? 90 as an oil phase, Cremophor^® RH40 as a surfactant, and Transcutol^® HP as a co-surfactant. All tested formulations were thermodynamically stable with globule sizes ranging from 13.74 to 29.19?nm and emulsification time not exceeding 1?min, indicating the formation of homogenous stable nanoemulsions. In vitro drug release showed significant enhancement from L-SNEDDS formulations compared to aqueous drug suspension. Optimized L-SNEDDS showed significantly higher intestinal permeation compared to plain drug solution with nearly 1.6–2.9 folds increase in the apparent permeability coefficient as demonstrated by the ex vivo studies.

Conclusions: The present study proved that AMS could be successfully incorporated into L-SNEDDS for improved dissolution and intestinal permeation leading to enhanced oral delivery.     

Evaluation of Permeability Through Permeation Experiments: Isostatic and Quasi-isostatic Methods Compared

Isostatic and quasi-isostatic permeation experiments were used to characterize the permeability of 1-hexanol through polypropylene films. The quasi- isostatic method was considered as an isostatic experiment at the limit a of null purging stream flow rate. Permeability values obtained through the isostatic method showed dependency on the purging stream flow rate. The extrapolated value at zero purging stream flow rate is in agreement with the data obtained via the quasi-isostatic procedure. Diffusion coefficient values were also determined. The isostatically obtained diffusion coefficients behave similarly to P. However, the value at zero flow rate differs significantly from the value obtained through the quasi-isostatic method. From these results the validity of permeation experiments for the evaluation of the diffusion coefficient is questioned.     

Design of antihistaminic transdermal films based on alginate–chitosan polyelectrolyte complexes: characterization and permeation studies

The purpose of this study was to develop suitable matrix-type transdermal drug delivery systems of Ketotifen fumarate (KF) as antiasthmatic drugs. Chitosan–alginate polyelectrolyte complex (PEC) films were used as drug release regulators for KF. Antihistaminic films with variable PEC compositions were prepared using different ratios of chitosan (CTS) to sodium alginate (ALG). Propylene glycol (PG) was used as plasticizer; Tween 80 (T₈₀) and Span 20 (S₂₀) were used as permeability enhancers. Nine formulations were obtained by film casting method and characterized in terms of weight uniformity, thickness, folding endurance, moisture lost, and moisture absorption. In addition, drug release and permeation through rat abdominal skin mounted in Franz cell were investigated. All formulations were found to be suitable in terms of physicochemical characteristics, and there was no significant interaction between the used drug and polymers. It was noticed that when T₂₀ is used as permeation enhancer, a satisfactory drug release pattern was found where 99.88% of drug was released and an amount of 2.121?mg/cm² of KF was permeated after 24?h. For the optimal formulation, a permeability coefficient of 14.00?±?0.001?cm h^?1 and a latency time of 0.35?±?0.02?h were found. The in-vitro analysis showed controlled release profile which was fitted by Korsmeyer–Peppas model (R²?=?0.998). The obtained results suggested that new controlled release transdermal formulations of asthmatic drugs could be suitably designed as an alternative to the common forms.     

Thermal conductivity of liquid crystalline epoxy/BN filler composites having ordered network structure

BN filler was added to a liquid crystalline (LC) epoxy resin to obtain a high thermal conductive material. The LC epoxy/BN composites, which were cured at different temperatures, formed an isotropic or LC polydomain phase structure. The relationship between the network orientation containing mesogenic groups and the dispersibility of the BN filler was discussed. As a result, the thermal conductivity of the LC polydomain system was drastically enhanced even at a relatively low volume fraction of BN (30 vol%), regardless of the fact that both the LC and isotropic phase systems consisted of the same resin and filler content combination. This result is due to the formation of thermal conductive paths by the BN filler by exclusion of the BN filler from the LC domain formed during the curing process in the composite having the LC polydomain matrix.     

Preparation and study of aramid/epoxy prepregs

Solid epoxy resin compounds were studied for their suitability as matrices for the preparation and curing of prepregs containing aramid fibres. Acid anhydrides were shown to be incompatible to the epoxy resin, producing a dispersed crystalline phase upon drying, whereas o-phenylenediamine is a miscible cross-linking agent. Also, diamine is safer because it reacts with the epoxy at temperatures considerably higher than the anhydrides. Composite specimens prepared by these prepregs display similar tensile strength and lower modulus than those derived from the one-step process, by the use of conventional liquid epoxy systems.     

Peptide washout and permeability from glyceryl monooleate buccal delivery systems

Simultaneous evaluation of the permeation and washout of a peptide from the mucoadhesive liquid crystalline phases of glyceryl monooleate (GMO) has been investigated using a donor compartment flow-through diffusion cell. [D-Ala2, D-Leu5]enkephalin (DADLE) was incorporated into the cubic and lamellar liquid crystalline phases of GMO and applied to excised porcine buccal mucosa mounted in the donor compartment flow-through cell. Phosphate-buffered saline pH 7.4 (PBS) was pumped across the upper surface of the liquid crystalline phases to mimic salivary flow. The steady-state fluxes of DADLE and GMO from the cubic phase were significantly greater than that from the lamellar phase (P < 0.01). There was no statistical difference between the amounts of DADLE and GMO washed out from the lamellar and cubic phases (P > 0.05). The donor compartment flow-through diffusion cell was found to be a useful tool to evaluate the impact of salivary washout on mucoadhesive oral mucosal delivery systems.     

Dihydrogenimidazole modified silica-sulfonated poly(ether ether ketone) hybrid materials as electrolyte membranes for direct ethanol fuel cells

The present study reports on dihydrogenimidazole modified inorganic-organic mixed matrix membranes for possible application as a proton exchange membrane in direct ethanol fuel cells. The polymeric phase consisted mainly of sulfonated poly(ether ether ketone) (sPEEK) with a sulfonation degree of 55%. The inorganic phase was built up from hydrophilic fumed silica particles interconnected with partially hydrolyzed and condensed tetraethoxysilane with a total inorganic loading of 27.3%. This inorganic phase was further modified with N-(3-triethoxysilylpropyl)-4,5-dihydroimidazole (DHIM), which consists of an hydrolyzable inorganic part and a functional organic group. The influence of the modifier on the mixed matrix system was studied by means of various modifier concentrations in various aqueous-ethanolic systems (water, 2 M and 4 M ethanol). Modifier concentration and ethanol concentration of the ethanol-water mixture exhibited significant but opposite effects on the liquid uptake of the mixed matrix membranes. The proton conductivity as well as the proton diffusion coefficient as a function of modifier content showed a linear decrease. The proton conductivity as a function of temperature showed Arrhenius behavior and the activation energy of the mixed matrix membranes was 43.9 ± 2.6 kJ mol⁻¹. High selectivity of proton diffusion coefficient to ethanol permeability coefficient was obtained with high modifier concentrations. At low modifier concentrations, this selectivity was dominated by ethanol permeation and at high modifier concentrations by proton diffusion. The main electrolyte properties can be optimized by setting the DHIM content in mixed matrix membrane. With this approach, tailor-made membranes can be prepared for possible application in direct ethanol fuel cells.     

Basil Oil is a Promising Skin Penetration Enhancer for Transdermal Delivery of Labetolol Hydrochloride

Thepresent work investigates effectiveness of basil oil, a volatile oil containing alcoholic terpenes, as a potential penetration enhancer for improved skin permeation of labetolol hydrochloride (LHCl) with reference to camphor, geraniol, thymol, and clove oil. Saturation solubilities of LHCl were determined in water, vehicle (ethanol:water, 60:40 v/v) and vehicle containing 5% w/v terpenes. Comparable (P > 0.05) saturation solubilities were found suggesting an insignificant increase in LHCl flux across rat skin on account of thermodynamic activity. Permeation of LHCl in vehicle per se and in presence of 5% w/v enhancer was investigated by performing in vitro rat abdominal skin permeation studies using a side-by-side glass diffusion cell. Various parameters viz. steady state flux, permeability coefficient, lag time, partition coefficient, diffusion coefficient, and enhancement ratios (ER) were calculated from the permeation data. Basil oil produced the maximum enhancement (ER?=?46.52) over neat vehicle, among all enhancers. Activation energies for LHCl permeation in water, vehicle per se and in presence of 5% w/v basil oil were found to be 23.16, 18.71, and 10.98 kcal/mole, respectively. Lowering of activation energy in presence of basil oil suggests creation of new polar pathways in the skin for enhanced permeation of LHCl. Basil oil is proposed as a promising penetration enhancer for improved transdermal drug delivery of labetolol.     

Diffusion and permeation of vapors in composite polymer thin films

The moisture barrier properties of polyimide (PI) thin films used for passivation in microelectronic devices are poorer than those of many other polymers. The enhancement of the barrier properties of PI films obtainable by coating them with polymers of lower permeability to form multilayer composite membranes was investigated. In this paper we report a study of the diffusion and permeation of water vapor in four composite PI/polymer thin films: PI/polyethylene, PI/polyethylene-acrylic acid, PI/polyvinylidene fluoride and PI/poly(chloro-p-xylylene). The temperature-dependent permeability coefficient of single-layer and composite thin films was measured and found to follow the Arrhenius relation with low activation energies (lower than 6 kcal mol^?1). Enhancement in the barrier properties by a factor of 4–6 at 30°C is attained when 2–3 μm PI films are coated with 2 μm films of the four polymers investigated.     

Measurement of permeability for packaging films to d-limonene vapour at low levels

A method that utilizes permeation cells in conjunction with gas chromatography was developed to measure permeation of d-limonene vapour through packaging materials at very low gradient concentrations. The same method, when properly adjusted, can be used to determine the effect of temperature and relative humidity on permeation. The suitability of the method for its intended use was demonstrated by generating permeation data for polyester (Mylar) and oriented polypropylene (OPP) films at d-limonene vapour concentration gradients as low as 0.54 ppm. The ability to measure permeability at such low concentration levels, where the permeability coefficient approaches a virtually constant value, is of considerable importance. The permeation behaviour of packaging materials at even lower concentrations, most typical of foods, can be obtained by extrapolation. Thus, flavour loss through the package and shelf-life can be estimated in a more reliable manner.