Permeation Lag Time Research Articles

Plant leaf mucilage/carrageenan/Eudragit® NE30D blended films: Optimization, characterization, and pharmaceutical application

Mucilage of C. pareira leaves was utilized, being manufactured for use in pharmaceutical products. Carrageenan and Eudragit® NE30D were used to combined. Glycerin was used as a plasticizer at a concentration of 20 % w/w based on the amount of polymer used. Computer software optimized its characteristics, including tensile properties, moisture uptake, and erosion; the optimal formulation was 1.4:1.2:2.8. The percentages of optimization error ranged from 8.48 to 13.80 %. Propranolol HCl was mixed to an optimal formulation. The film layer was tight, homogeneous, and smooth, with no holes. DSC thermogram showed no interaction peaks at 101.33 °C and 170.50 °C. Propranolol HCl concentration in the film ranged from 2.18 to 2.20 mg/cm2. Propranolol HCl was quickly released from the film. The kinetic model for the release profile was first-order kinetic. Although propranolol HCl had a high-release profile, its skin permeation was limited. The permeation lag time, Jss, and Kp were 1.60–2.65 h, 0.0182–0.0338 μg/cm2/h, and 9.10–15.35 cm/h, respectively. A significant amount of propranolol HCl residue was found on the skin's surface. Glycerin appeared to influence propranolol HCl permeability. Therefore, the plant leaf mucilage/carrageenan/Eudragit® NE30D blended film can be utilized in pharmaceutical applications to control drug release from its film layer.

Predicting vapour transport from semi-volatile organic compounds concealed within permeable packaging

The vapour concentration present in enclosed spaces containing concealed semi-volatile organic compounds (SVOCs), such as explosives, is difficult to measure experimentally. Therefore, mathematical models play a key role in understanding the transport of these materials. Vapour transport has previously been modelled in a range of environments, from small emission cells to whole rooms, using both analytical and numerical approaches. These models typically include either a well-mixed air volume or a simple sorption model. This work has been extended by including a multi-layer vapour sorption/permeation model within a computational fluid dynamics (CFD) framework. This allows for vapour source terms from items concealed within permeable packaging to be considered. The CFD based permeation model includes sorption/desorption, using a linear isotherm at inner and outer surfaces and a blended wall function to account for the effects of near-wall turbulence. The model has been validated for the explosive SVOC, ethylene glycol dinitrate (EGDN). The model has been used to show how vapour concentrations around a cardboard box containing a SVOC vary when some of the key input parameters are changed. Changing the vapour source from EGDN to the much lower vapour pressure trinitrotoluene (TNT), had a significant effect, as expected, and this was most pronounced early on due to the difference in permeation lag times for the two materials. Conversely, changing the type of cardboard had only a small effect on the concentrations. This type of modelling approach can now be used to study a wide range of SVOC transport problems which would not previously have been possible.

Soluplus micelles for acyclovir ocular delivery: Formulation and cornea and sclera permeability

Nearly 20% of people affected by the herpes simplex virus (HSV) suffer from vision problems. The virus can infect all layers of the cornea or cause inflammatory diseases of the sclera. The aim of this work was to test whether encapsulation of acyclovir in Soluplus or Solutol polymeric micelles increases its solubility, corneal permeability and sclera penetration. The aqueous solubility of acyclovir is known to be low, and therefore approaches that increase both its solubility and ability to penetrate through the eye may favor the efficacy of the treatments. Copolymer dispersions (covering wide range of concentrations) were prepared in water and PBS 7.4 and characterized regarding size and Z-potential (close to zero). Solutol micelles increased their size when the drug was incorporated (135 vs. 19 nm), while Soluplus micelles showed little difference (137 nm). Only Soluplus micelles significantly enhanced acyclovir solubility and withstood dilution stability tests. Soluplus (12–20%) formulations showed a progressive increase in viscoelasticity as temperature rose, which may allow for easy dropping onto the eye and subsequent retention in the gel form. Drug permeability through bovine cornea and sclera was investigated in detail. Although similar permeability coefficients were recorded for the drug when applied as the free drug in solution or formulated in Soluplus micelles, the micelle formulation significantly shortened the permeation lag time through the cornea. Moreover, Soluplus micelles were advantageous compared to the drug solution in terms of greater amount of acyclovir accumulated in both cornea and sclera, and higher steady state flux. If compared with cornea, the amounts of drug permeated through the sclera were approx. 10 times greater, which opens the possibility of drug delivery to the posterior eye segment.

Enhanced Transdermal Peptide Delivery and Stability by Lipid Conjugation: Epidermal Permeation, Stereoselectivity and Mechanistic Insights

Efficient delivery of therapeutic peptides to the skin will facilitate better outcomes in dermatology. The tetrapeptide AAPV, an elastase inhibitor with potential utility in the management of psoriasis was coupled to short chain lipoamino acids (Laa: C6-C10) to enhance the peptide permeation into and through human epidermis. AAPV was conjugated to Laas by solid phase synthesis. Peptide stability, skin distribution and permeation, elastase activity and surface activity were determined. Laas increased peptide permeation into the skin. The permeation lag time and amount of peptide remaining in the skin increased with the carbon chain length of the Laa conjugate. We also demonstrated stereoselective permeation enhancement in favour of the D-diastereomer. Importantly, the elastase inhibition activity of the peptide was largely retained after coupling to the Laa conjugates, showing potential therapeutic utility. The Laa-peptide structures were shown to be surface active, suggesting that this surfactant-like activity coupled with enhanced lipophilicity may contribute to their interaction with and permeation through the lipid domains of the stratum corneum. This study suggests that the Laa conjugation approach may be useful for enhancing the permeation of moderately sized peptide drugs with potential application in the treatment of skin disorders.

Enhancement Effect of Trypsin on Permeation of Clindamycin Phosphate Through Third-degree Burn Eschar.

Antimicrobial therapy remains to be the most important method of wound infection treatment. Systemically administered antimicrobials may not achieve therapeutic level in wound. On the other hand, in the absence of surgical debridement (due to any reason), most topically applied antimicrobials cannot penetrate the wound in therapeutic amount due to the presence of eschar. Burn eschar is a proteinous structure with some lipid components in which proteins seems to play an important role in the barrier effects of eschar. Therefore, in this study the effect of protein-acting enhancer (trypsin) on permeation of hydrophilic model drug (clindamycin phosphate) was investigated. To perform this investigation, permeation of saturated clindamycin phosphate was studied at 32°C through trypsin-treated and untreated eschar samples for 12 h using home-made static diffusion cells. Third-degree burn eschar samples were separated at the time of surgical debridement (7-14 days post burn) from burned patients. Before each experiment, eschar was hydrated for 12 h and samples were then treated with trypsin solution (1%, w/v) for 4 and 24 h. Clindamycin was measured by a HPLC method developed here. Results showed that after trypsin-treatment for 4 and 24 h, clindamycin phosphate permeation flux was increased significantly by about 1.5 and 2 times and permeation lag-time was decreased by about 2 and 1.3 times respectively. The present results show that permeation of drugs through burn eschar can be increased considerably by trypsin.

Deuterium permeation through carbon-coated tungsten during ion bombardment

Deuterium permeation during ion bombardment through tungsten membranes coated by amorphous carbon films was investigated and compared with the permeation through bare tungsten. The membrane was bombarded by D3+ ions with energies of 200 and 1200 eV/D at a temperature of 873 K. The thickness of the amorphous carbon film was 120–170 nm. Detailed characterization of the carbon films were performed using AFM, NRA, RBS, FIB/SEM and XPS. The influence of the carbon films on permeation were strong for both ion energies, but different for each energy. In the case of 200 eV/D ions, the film was completely removed by the end of permeation due to intensive chemical sputtering, the lag time of permeation was much longer than for the bare membrane, and the permeation rate rose to a maximum value close to the bare membrane and then decreased to lower values. In the case of 1200 eV/D, the films were sputtered only very slowly, the lag time was much longer than in the case of the bare membrane but shorter than at 200 eV/D, and the permeation rate increased steadily up to several percents of the incident flux.

Determination of hydrogen diffusivity and permeability in W near room temperature applying a tritium tracer technique

Tungsten is a primary candidate of plasma facing material in ITER and beyond, owing to its good thermal property and low erosion. But hydrogen solubility and diffusivity near ITER operation temperatures (below 500K) have scarcely studied. Mainly because its low hydrogen solubility and diffusivity at lower temperatures make the detection of hydrogen quite difficult. We have tried to observe hydrogen plasma driven permeation (PDP) through nickel and tungsten near room temperatures applying a tritium tracer technique, which is extremely sensible to detect tritium diluted in hydrogen.The apparent diffusion coefficients for PDP were determined by permeation lag times at first time, and those for nickel and tungsten were similar or a few times larger than those for gas driven permeation (GDP). The permeation rates for PDP in nickel and tungsten were larger than those for GDP normalized to the same gas pressure about 20 and 5 times larger, respectively.

A fundamental investigation into the effects of eutectic formation on transmembrane transport

Eutectic systems enhance the permeation of therapeutic agents across biological barriers, but the mechanism by which this occurs has not previously been elucidated. Using human skin it has proven difficult to isolate the fundamental effects of eutectic formation on molecule diffusion and partition from those that arise as a consequence of the simultaneous application of two agents. The aim of this work was to employ a model hydrophobic membrane to understand the fundamental permeation characteristics of two agents when applied as a eutectic mixture. Lidocaine and prilocaine were selected as model agents and infinite-dose permeation studies were carried out using pre-calibrated Franz diffusion cells with two thicknesses of silicone membrane. Membrane solubility was determined by HCl solution extraction and the membrane diffusion coefficients were calculated from the permeation lag-times. The maximum permeation enhancement was achieved using a eutectic mixture at a 0.7:0.3 prilocaine/lidocaine ratio. A higher solubility of both agents in silicone membrane, enhanced diffusivity of prilocaine and superior release of both drugs, all contributed to produce enhanced permeation from the eutectic mixtures. Deconvolution of the transmembrane transport process suggests that the eutectic enhancement phenomena is a consequence of more favorable permeation characteristics of the two molecules in the absence of a formulation vehicle which competes in the transport process.

Modeling of transient hydrogen permeation process across a palladium membrane

Transient mass transfer processes of hydrogen permeating through a Pd membrane are modeled to aid in predicting the hydrogen transport behavior. The model is established in terms of the quasi-steady time and the steady permeation rate. Meanwhile, four important parameters are considered; they are the permeation lag time, the initial permeation rate, the concave up period and the concave down period. A unit step function is embedded in the model to account for the effect of the hydrogen permeation lag at a lower pressure difference. Corresponding to the lower, the moderate and the higher pressure differences (i.e. 3, 5 and 8 atm), though the hydrogen permeation undergoes a three-stage, a two-stage and a one-stage processes, respectively, these processes can be predicted well by an arc tangential function. By introducing an adjusting parameter in the arc tangential function, there exists an optimal value of the adjusting parameter when the pressure difference is lower. In regard to the moderate and higher pressure differences, the predictions agree with experiments well if the adjusting parameter is sufficiently large. Physically, the unit step function is used to account for the controlling mechanisms of hydrogen diffusion toward the membrane and the spillover of the hydrogen across the membrane. The initial jump parameter represents the rapid response of the initial hydrogen permeation. The adjusting parameter can be used to describe the relative importance of the concave up and the concave down periods.

Preparation of matrine ethosome, its percutaneous permeation in vitro and anti-inflammatory activity in vivo in rats

The aim of this work was to evaluate the preparation of matrine ethosome and the percutaneous permeation in vitro and the anti-inflammatory activity in vivo in the rat skin. The matrine ethosomes were prepared by the ethanol injection-sonication method. The particle size of the ethosomes was measured by a laser particle-size analyzer, and the entrapment efficiency was detected by ultracentrifugation. The anti-inflammatory activity in vivo of the matrine formulations was determined by a reflection spectrophotometer. In this study, we found that the average particle size of matrine ethosomes was in the range of 50–200 nm with a narrow distribution, and the entrapment efficiency was in the range of 40–90%. Compared with other formulations, matrine ethosomes had the largest 24-hour accumulative permeation quantity (60.5%) and with no permeation lag time. Matrine ethosomes were able to make the induced erythema disappear more rapidly than the nonethosomes formulations of matrine. This study reveals that the average particle size of matrine ethosomes decreases with the increase of ethanol concentration and increases with the increase of phospholipid concentration, while the entrapment efficiency increases with the increase of the concentration of both ethanol and phospholipid. Matrine ethosomes can increase the percutaneous permeation of matrine in the experiment in vitro and improve the anti-inflammatory activity of matrine in vivo in rat skin.

Enhancement effect of terpenes on silver sulphadiazine permeation through third-degree burn eschar

Antimicrobial therapy remains one of the most important methods of wound management. Systemically administered antimicrobials may not achieve therapeutic levels in wound and most agents cannot penetrate burn eschar well enough when applied topically. Therefore, we tested the notion to increase permeability of eschar toward topical agents using terpenes, a well-known class of skin permeation enhancers. Four terpenes, limonene (hydrocarbon), eucalyptol (ether), α-pinene oxide (epoxide) and geraniol (alcohol) were chosen and their effects on permeation of silver sulphadiazine (SSD), a widely used topical antimicrobial agent, through human third-degree burn eschar was evaluated using static diffusion cells. Results showed that terpenes increased permeation flux of SSD through eschar significantly ( P < 0.0001). Limonene provided the highest flux enhancement ratio (9.0 times), followed by geraniol, eucalyptol and α-pinene oxide with enhancement ratios of 5.5, 4.7 and 4.3 respectively. The effects of terpenes on permeation lag-time, was less than 20%. Data analysis revealed that terpenes increase permeation of SSD mainly by increasing its partitioning into the eschar. The present results show that permeation of drugs through burn eschar can be increased considerably by terpenes and that burn wound antimicrobial therapy may be improved by terpenes and possibly other penetration enhancers.

Ion-driven deuterium permeation through tungsten at high temperatures

The ion-driven permeation (IDP) through 50 μm thick pure tungsten foils was measured in the temperature range of 823–923 K during irradiation by 200 eV/D + ion beam with a flux of 10 17–10 18 D/m 2s. Gas driven permeation (GDP) from the deuterium background gas was observed as well. Calculations using both the analytical formula for the diffusion limited regime (DLR) and the TMAP 7 code gave good agreement with the experimental data. Defects with a detrapping energy of (2.05 ± 0.15) eV were found to limit the permeation lag time in our experimental conditions.

SMGA gels for the skin permeation of haloperidol

Small molecule gelling agent (SMGA) gels were developed using the gelator GP-1 in the solvents, namely, isostearyl alcohol (ISA) and propylene glycol (PG), to deliver haloperidol through the skin. The concentrations of the drug, haloperidol, the enhancer, farnesol and the gelator, GP-1 are 3 mg/ml, 5% (w/v) and 5% (w/v), respectively. The study employed a three-factor full factorial statistical design to investigate the influence of factor level changes on the permeability coefficient and permeation lag-time of haloperidol. Gels were prepared by raising temperature to 120 °C, followed by natural cooling under room temperature of 22 ± 1 °C. The rheological properties of the gels were examined with a strain-controlled dynamic mechanical method. The in vitro permeation study was conducted with automated flow-through type cells. The gels successfully incorporated the drug and enhancer without losing their aesthetic properties. The in vitro human skin permeation study showed the permeation of the drug in ISA-based gels reached the pseudo steady state faster than PG-based gels and were less affected by gelator. PG-based gels delivered the drug at a faster rate with the incorporation of the enhancer. GP-1 did not influence the drug permeation rate but it increased permeation lag-time. The co-existence of gelator or enhancer increased the lag-time to a larger extent than when used separately. The novel SMGA gels are suitable for topical or transdermal delivery.

Enhancement Effect of p‐Menthane‐3,8‐diol on In Vitro Permeation of Antipyrine and Indomethacin Through Yucatan Micropig Skin

The enhancing effect of p‐menthane‐3,8‐diol (MDO) on skin permeation of antipyrine (ANP) and indomethacin (IM) through Yucatan micropig skin in vitro was compared with l‐menthol. p‐menthane‐3,8‐diol is a metabolite of l‐menthol and has little odor. It is easy to combine the vehicle because of lower lipophilicity than l‐menthol. All formulations contained 40% (v/v) ethanol. The permeation of ANP increased with MDO about three times that without enhancer by increasing ANP concentration in the skin. However, the MDO effect was about a quarter that of l‐menthol. The permeation of IM with MDO was about 15 times that with no enhancer and it was almost the same as that with l‐menthol. The lag time of permeation was not significantly changed by MDO, which was not so in the case of l‐menthol. Skin concentration of IM increased about 11 times and six times with MDO and l‐menthol, respectively. MDO and l‐menthol partitioned to the skin relatively high concentrations, 5.9 and 2.5 mg/cm3, respectively. The solubility of IM in the skin was improved by MDO, and consequently, the permeation of IM was enhanced.

Stereoselective Permeation of Tretinoin and Isotretinoin through Enhancer-Treated Rat Skin. II. Effects of Lipophilic Penetration Enhnacers

Many properties of chemicals depend on their stereochemistry. Among these, the effects of stereoisomerism on percutaneous absorption of drugs are not well studied. We have previously shown that permeation of tretinoin and isotretinoin (two geometric isomers) through hydrophilic enhancers-treated rat skin is stereoselective. As, depending on their lipophilicity, penetration enhancers can change permeation pathway of drugs, it was decided here to investigate permeation of the same stereoisomers through lipophilic enhancer-treated skin. Oleic acid, that mainly affects stratum corneum intercellular lipids, was chosen as the lipophilic penetration enhancer for this study. Permeation of retinoids through untreated and enhancer-treated rat skin was studied at room temperature. These studies employed static diffusion cells, saturated drugs in propylene glycol:water mixture (75:25, v/v) as the donor phase and aqueous solution of Tween20 as the receptor phase. Permeation of retinoids through untreated skin was too low to be detected in the receptor phase even by the used HPLC method with sensitivity of 10 ng ml -1 . Oleic acid increased the permabilities of retinoids to measurable values. In oleic acid-treated skin, tretinoin permeated by about 1.3 times faster than isotretinoin (P<0.0001). However, permeability coefficients, that are concentration-normalized fluxes, showed a reverse order. Permeability coefficient of isotretinoin through the same membrane was significantly (P=0.0002) higher than that of tretinoin. On the other hand, the difference between permeation lag-times of retinoids was not that significant (P=0.062). These data show that stereoselctive permeation of these retinoids through oleic acidtreated rat skin is mainly a partitioning-related phenomenon. Diffusion coefficient might play only a minor role. Present results are partly different from those of our previous study on hydrophilic enhancers and clearly show that the type of enhancer and its mode of action can affect stereoselective permeation of drugs through the skin.

Comparison of skin permeation enhancement by 3- l-menthoxypropane-1,2-diol and l-menthol: the permeation of indomethacin and antipyrine through Yucatan micropig skin and changes in infrared spectra and X-ray diffraction patterns of stratum corneum

3- l-Menthoxypropane-1,2-diol (MPD) is a derivative of l-menthol, which has an enhancement effect on drug permeation through skin. In this study, the effect of MPD on drug permeation through skin was compared with that of l-menthol. MPD or l-menthol at final concentrations of 3% in 40% ethanol was added to the drugs indomethacin or antipyrine and each mix then applied to Yucatan micropig skin in vitro. Drug concentrations in the skin were higher in the presence of either MPD or l-menthol, however, only l-menthol shortened the lag time of permeation. MPD enhanced the skin permeation of the drugs only by increasing the skin concentration of the drugs. In contrast, l-menthol enhanced the skin permeation of the drugs by increasing both the skin concentration and the diffusion rate in skin. The infrared (IR) spectra and X-ray diffraction patterns of stratum corneum after treatment with MPD did not differ from those of intact stratum corneum. A change in the IR spectra of stratum corneum after treatment with l-menthol was observed at the CH band, and the peaks representative of the lipid structure in the X-ray diffraction patterns decreased in intensity. These results suggest that l-menthol, but not MPD, disrupts the intercellular lipid structure of stratum corneum. Thus, MPD is expected to be a moderate skin permeation enhancer.

Heparin penetration into and permeation through human skin from aqueous and liposomal formulations in vitro

The transport of unfractionated (UH) and low molecular weight Heparin (LMWH) in human skin was investigated in vitro using heat separated epidermal membrane and dermis and the effect of liposomal formulations with Phospholipon® 80 (PL80) and Sphingomyelin (SM) was assessed. The distribution of Heparin within skin tissue was studied by the tape stripping method. Heparin concentrations were measured with a biological assay. Transepidermal water loss was determined to characterize barrier properties of skin. No consistent permeation of Heparin through epidermal membrane was detected. Penetration into the epidermal membrane was for LMWH significantly greater than for UH. Accumulation of UH was largely restricted to the outermost layers of the stratum corneum while LMWH penetrated into deeper epidermal layers. UH penetration into epidermis was detected for the PL80 liposomal formulation only. The extent of LMWH penetration was independent of the formulation, LMWH, however, showed a trend to accumulate in deeper epidermal layers for the PL80 compared to the aqueous formulation. Thus, molecular weight and liposomal formulations influenced the penetration pattern of Heparin in the epidermis. It can not be concluded whether the concentration of LMWH achieved at the blood capillaries is sufficient to exert a pharmacological effect. UH permeated readily through dermis irrespectively of formulation and its accumulation in the dermis was significantly enhanced and its lag time of permeation increased in the presence of SM liposomes.

Dermal drug delivery — Improvement by choice of vehicle or drug derivative

Propylene glycol was found to easily permeate human skin in vitro, and its accelerating effect on metronidazole permeation could be ascribed to a possible “carrier-solvent” effect. Incorporation of Azone ® in propylene glycol vehicles enhanced the permeation rate by decreasing the lag time of permeation of the drug as well as propylene glycol from the vehicle. This effect of azone lasted for the subsequent application of the drug where ozone was omitted from the vehicle, indicating that the accelerant might modify the cutaneous barrier in vitro. Pro-drug derivatives of metronidazole and of 5-fluorouracil have been developed which permit increased cutaneous drug permeation and simultaneously undergo conversion to the parent drug by the cutaneous hydrolytic enzymes. Enzyme-mediated hydrolysis by a human skin homogenate of aliphatic esters of metronidazole is presented.

Drug Permeation through Membranes II: Simultaneous Dissolution and Permeation of Drug from Solid Dosage Forms

<h2>Abstract:</h2> The simultaneous dissolution and permeation of a drug from solid oral dosage forms were analyzed by a treatment based on Fick's second law of diffusion. The analysis shows that dissolution rate constants can be obtained from the permeation lag time, while the coefficients of permeability are estimated, as usual, from the rate of drug transfer across the membrane under steady-state conditions. Drug-excipient interactions, if any, would be expected to affect the rate of drug transfer across the membrane. Therefore, from a single experiment, the dissolution rate and the extent of drug-excipient interaction can be obtained. The equation was tested by dissolution-permeation measurements on two amobarbital formulations.