Percutaneous Permeation Of Drugs Research Articles

Effect of invasome composition on membrane fluidity, vesicle stability and skin interactions

Invasomes have been widely exploited to enhance the percutaneous permeation of drugs. On the other hand, few studies have been dedicated to evaluating how their composition impacts the interaction with the skin, vesicle rigidity and stability, which was the focus of this investigation. Light scattering and spectroscopic techniques were considered for vesicle characterization. The addition of cholesterol (CHOL) into the phosphatidylcholine (PC) vesicles led to increased membrane rigidity (from PC:CHOL 5:0.5) and a concentration-dependent disorder effect on skin domains. Nevertheless, these vesicles were showed to be less stable. Ethanol, in turn, resulted in larger and more flexible vesicles, which can be attributed to its preferential distribution in headgroups of PC. The effect of limonene on membrane rigidity was dependent on the vesicle composition. It reduced the rigidity when few constituents were considered, but an opposite effect was observed for vesicles containing PC, CHOL, ethanol and limonene. Competitive effects of limonene and CHOL by the same domains in PC could explain these findings. Limonene was crucial to obtaining more monodisperse vesicles and it showed a synergistic action with CHOL in the disruption of lipid domains in the skin. Invasomes were more stable than liposomes. CHOL-free invasomes showed to be stable for up to 40 days at room temperature.

In vitro and in vivo trans-epidermal water loss evaluation following topical drug delivery systems application for pharmaceutical analysis

The measurement of Trans-Epidermal Water Loss (TEWL) allows to evaluate the integrity of Stratum Corneum Epidermis (SCE) barrier after topical application of colloidal nanocarriers by using a non-invasive method. The temporarily modifications of SCE lipids are important for the passage of colloidal nanocarriers across the skin; this passage causes a modification of TEWL values. Niosomes, ethosomes®, and transfersomes® are used as topical drug delivery systems due to their biopharmaceutical properties, and capability to permeate intact through the SCE. In vitro and in vivo evaluation of TEWL values was studied for niosomes, ethosomes® and transfersomes® in occlusive and non-occlusive conditions. TEWL values in vivo, using healthy human volunteers, are ∼12 g/m2∙× h for all nanoformulations after 72 h, due to the rearrangement of lipids forming the SCE membranes. Conversely, TEWL values of healthy human volunteers, that are topically treated with niosomes, ethosomes® and transfersomes®, in non-occlusive conditions, are ∼20 g/m2∙× h. This data was lower than those obtained in occlusive conditions (∼35 g/m2∙× h). In vitro studies agreed results which are obtained in occlusive conditions using healthy human volunteers. SCE lipids of the skin restore their native structure after 72 h of nanocarrier application. In vitro and in vivo results showed that niosomes, ethosomes®, and transfersomes® interact with the skin in a temporary and reversible mode, and they can be used as suitable colloidal nanocarriers to increase the percutaneous permeation of drugs after topical application without damaging the native structure of the skin.

An evaluation of crude palm oil (CPO) and tocotrienol rich fraction (TRF) of palm oil as percutaneous permeation enhancers using full-thickness human skin

The drawbacks associated with chemical skin permeation enhancers such as skin irritation and toxicity necessitated the research to focus on potential permeation enhancers with a perceived lower toxicity. Crude palm oil (CPO) is obtained by direct compression of the mesocarp of the fruit of the oil palm belonging to the genus Elaeis. In this research, CPO and tocotrienol-rich fraction (TRF) of palm oil were evaluated for the first time as skin permeation enhancers using full-thickness human skin. The in vitro permeation experiments were conducted using excised human skin mounted in static upright ‘Franz-type’ diffusion cells. The drugs selected to evaluate the enhancing effects of these palm oil derivatives were 5-fluorouracil, lidocaine and ibuprofen: compounds covering a wide range of Log p values. It was demonstrated that CPO and TRF were capable of enhancing the percutaneous permeation of drugs across full-thickness human skin in vitro. Both TRF and CPO were shown to significantly enhance the permeation of ibuprofen with flux values of 30.6 µg/cm2 h and 23.0 µg/cm2 h respectively, compared to the control with a flux of 16.2 µg/cm2 h. The outcome of this research opens further scope for investigation on the transdermal penetration enhancement activity of pure compounds derived from palm oil.

Inhibitory activity of limonene against Leishmania parasites in vitro and in vivo

Limonene is a monoterpene that has antitumoral, antibiotic and antiprotozoal activity. In this study we demonstrate the activity of limonene against Leishmania species in vitro and in vivo. Limonene killed Leishmania amazonensis promastigotes and amastigotes with 50% inhibitory concentrations of 252.0 ± 49.0 and 147.0 ± 46.0 μM, respectively. Limonene was also effective against Leishmania major, Leishmania braziliensis and Leishmania chagasi promastigotes. The treatment of L. amazonensis-infected macrophages with 300 μM limonene resulted in 78% reduction in infection rates. L. amazonensis-infected mice treated topically or intrarectally with limonene had significant reduction of lesion sizes. A significant decrease in the parasite load was shown in the lesions treated topically with limonene by histopathological examination. The intrarectal treatment was highly effective in decreasing the parasite burden, healing established lesions and suppressing the dissemination of ulcers. Limonene presents low toxicity in humans and has been shown to be effective as an agent for enhancing the percutaneous permeation of drugs. Our results suggest that limonene should be tested in different experimental models of infection by Leishmania.

Microneedle-based drug delivery: studies on delivery parameters and biocompatibility

There is a significant interest in the application of microneedles in intradermal drug delivery systems. Previous studies have demonstrated that skin permeation of drugs can be increased by orders of magnitude with microneedle insertion. In this study, emphasis is placed on the development of low cost, painless intradermal microneedle systems that can enhance the percutaneous drug permeation. Microneedles of octagonal pyramidal shape with the length of 150 mum were employed, and the capabilities of skin permeation enhancement under different delivery conditions were examined. The delivery parameters taken into account included the insertion time and the area of insertion. It was found that when solid microneedle arrays of 150 mum in length were pierced into human dermatomed skin for 5 to 60 s, microconduits with the depth of 50 to 80 mum were created to facilitate the percutaneous permeation of drugs. In percutaneous tests, it was demonstrated that the permeability coefficient of calcein (MW = 622.55) was significantly increased by 10(4) to 10(5) times compared to that on intact skin. In terms of biocompatibility, biological evaluation indicated a broad spectrum of safety for the microneedle system. These results suggest that the octagonal pyramidal microneedles can be an effective tool in developing novel intradermal drug delivery system.

Innovations in Transdermal Drug Delivery: Formulations and Techniques

The transdermal route of drug delivery has attracted researchers due to many biomedical advantages associated with it. However, excellent impervious nature of skin is the greatest challenge that has to be overcome for successfully delivering drug molecules to the systemic circulation by this route. Various formulation approaches used to systemically deliver drug molecules include use of prodrugs/lipophilic analogs, permeation enhancers, sub saturated systems and entrapment into vesicular systems. Further, the adhesive mixture, physical system of the delivery system and release liner influence drug release and its permeation across the skin. In addition, great strides in designing delivery systems for maximizing percutaneous drug permeation without comprising with ease of therapy cannot be neglected in improving functionality of transdermal drug delivery systems. This article deals with the innovations pertaining to formulation and techniques as described in recent patents.

FC‐57 Interspecies differences in the percutaneous permeation of substances with various lipophilicities

In veterinary medicine, the percutaneous permeation of drugs has relevance to therapeutic and forensic problems. It is commonly investigated in Franz diffusion cells using the excised skin of different mammalian species. Drug permeation characteristics through skin are considered to be significantly influenced both by the biochemical constitution of the stratum corneum and by the number and depth of hair follicles. Drug absorbance characteristics thus show a marked interspecies variance. This complicates the comparison of results obtained in different studies using different species. We examined the species influence on permeation parameters of three test compounds with different lipophilicities (benzoic acid, caffeine and testosterone) in Franz diffusion cells under standardized conditions. While testosterone was found to have the highest permeation coefficient, the permeation coefficients of benzoic acid and caffeine were lower and similar in all species. As expected, the absolute permeabilities showed marked interspecies differences, but the order of permeabilities of the test compounds was conserved in all species. The intraindividual coefficient of variation showed no significant difference between the examined species; the interindividual variation was significantly less marked in bovine skin than in other species. We conclude that the skin of different species can be used for the examination of skin permeation. However, results are transferable to other species only if they were obtained under standardized test conditions. Funding: German Federal Ministry of Education and Research.

The effects of terpene enhancers on the percutaneous permeation of drugs with different lipophilicities

Four model drugs were selected based on their lipophilicity denoted as log P (nicardipine hydrochloride log P −0.99±0.1, hydrocortisone log P 1.43±0.47, carbamazepine log P 2.67±0.38, and tamoxifen log P 7.87±0.75). The enhancing activities of four terpene enhancers (fenchone log P 2.13±0.30, thymol log P 3.28±0.20, d-limonene log P 4.58±0.23, and nerolidol log P 5.36±0.38) were tested in vitro across full thickness hairless mouse skin with each of the evaluated drugs formulated in hydroxypropyl cellulose gel formulations. The relationships between lipophilicity (log P) of the terpene enhancers and model drugs and efficacy (represented by the enhancement ratio of flux ER flux) of the drugs when coadministered with the enhancers were examined using linear regression. Terpene enhancers had significant effect on the percutaneous permeation of the model drugs. Nerolidol (highest lipophilicity) provided the highest increase in the flux of the evaluated model drugs. The flux of nicardipine hydrochloride increased by approximately 135-fold, hydrocortisone by 33-fold, carbamazepine 8-fold, and tamoxifen 2-fold. The lowest increase in the flux was observed with fenchone. Linear relationships were generated between the ER flux of nicardipine hydrochloride, hydrocortisone, carbamazepine, and tamoxifen and the log P of the terpene enhancers [ r=0.951, ( P=0.049), r=0.977, ( P=0.023), r=0.942, ( P=0.057), and r=0.874, ( P=0.126), respectively]. Furthermore, the four terpene enhancers produced linear relationships, indicating that they were more effective at enhancing the penetration of hydrophilic drugs rather than lipophilic drugs r=−0.824 ( P=0.176) for fenchone, r=−0.891 ( P=0.109) for thymol, r=−0.846 ( P=0.154) for limonene, and r=−0.769 ( P=0.232) for nerolidol.

Application of kinetic model to in vitro percutaneous permeation of drugs

Kinetic model using inter-compartmental rate constants, for permeation of drug across stratum corneum (k 1), for permeation across viable tissue layer of epidermis (k 2), and for back transfer of drug from viable tissue layer into the stratum corneum (k 3), was applied to in vitro percutaneous permeation process. Permeation data of four drugs, propranolol (PR), triamcinolone acetonide (TA), physostigmine (PHY), and tetrahydroaminoacridine (THA), previously studied across two skin membranes, hairless mouse skin (HMS) and human cadaver skin (HCS) were fitted to the permeation equation based on the kinetic model to obtain optimized values of the rate constants. The permeation profiles were also analyzed by the lag time method to estimate steady state flux (J ss), lag time (T lag), diffusion coefficient (D) and Skin/donor-phase partition coefficient (Km). The D and Km were used to regenerate the entire permeation profile (pre-steady and steady states) using equation based on Fick's laws of diffusion. The kinetic and diffusion models were compared by fits of the observed data to the model predicted values by linear regression, and obtaining R 2 and sum of squared deviations (SSD). Permeation data for all drugs across HMS or HCS, with or without the presence of permeation enhancer, were described very well by the kinetic model ( R 2 > 0.99), and the SSD's were smaller than that for the diffusion model except for THA. The rate of drug permeation across stratum corneum, k 0 (k 1 X Dose, amount of drug applied/cm 2 of skin in the donor phase) was similar to J ss as expected from the kinetic model. Diffusion coefficient of drug in the viable tissue (Dvt) ranged from 0.003–0.23 × 10 −7 cm 2/ s, similar to diffusion coefficient of similar sized molecules in protein gel as would be expected. Also, D vt was four orders of magnitude greater than D, the diffusion coefficient across stratum corneum, confirming stratum corneum to be the rate limiting barrier in the percutaneous permeation of the drugs studied. k 3 for all drugs were negligible indicating that no back diffusion of drug from viable tissue into the stratum corneum was occurring under the sink condition following infinite dose application. Also, except TA, none of the drug studied was lipophilic enough to be retained by the stratum corneum. Therefore, k 3 should not be used in the kinetic model for in vitro percutaneous permeation. For the PR 27-h, TA control and TA with 2% propylene glycol (PG) pretreatment experiments, the experiment duration was less than three T lag and steady state was not achieved, resulting in inaccurate estimates of D and Km and, hence, the regenerated profiles based on diffusion model did not describe the data well. However, kinetic model described these data also very well and SSD's were significantly smaller ( P = 0.05) than that for the diffusion model based regenerated profiles. The kinetic model is an alternative to diffusion model to describe the percutaneous permeation process, and the results presented here demonstrate the usefulness of the kinetic approach.

A METHOD FOR ASSESSING PERCUTANEOUS PERMEABILITY BY USING MODEL LIPIDS OF STRATUM CORNEUM

The maximum fluxes (Jmax) of six β-blockers across keratinized membranes were determined in vitro and compared with their melting points (mp). Rat abdominal skin and hamster cheek pouch mucosa were used as the model membranes. Linear relations of Jmax with mp were observed in both membrane. Permeation studies using the delipidized membranes and the isolated stratum corneum (SC) sheet of hamster cheek pouch clarified that the primary rate-limiting barrier function exists in the SC especially in the intercellular lipid. A lipid mixture system (ceramide : cholesterol : palmitic acid : cholesterol-3-sulfate = 40 : 25 : 25 : 10 by weight, a mimic of intercellular lipids of SC) was used as a lipid-coated membrane and liposomes to evaluate drug permeation through the SC. The Jmax values obtained in the lipid-coated membrane, which showed linear relations with those determined in rat skin and in hamster cheek pouch, correlated with the degree of drug partition to the liposomes prepared with the same model lipid mixture, suggesting the validity of this model lipid mixture system as an in vitro system substituted for animal skin in percutaneous drug permeation studies. The usefulness of the system in assessing the penetration enhancers which act on the lipids in the SC, such as oleic acid (OA), was also clarified.

Role of Intercellular Lipids in Stratum Corneum in the Percutaneous Permeation of Drugs

The effect of the depletion of intercellular lipids from human stratum corneum and shed snake skin on the permeability to salicylic acid (SA) was investigated in vitro. Shed snake skin was used as a model membrane for human stratum corneum. Lipid depletion with a mixture of chloroform and methanol increased the permeability of those skins to the ionized form but not to the unionized form of SA. Moreover, lipid depletion increased dramatically the permeability of shed snake skin to compounds with low lipophilicity, although it did not have a significant effect on the more lipophilic compounds. As a hypothesis to explain the marked increase of skin permeability to compounds of low lipophilicity, including the ionized form of SA, we suggest increased water transport.

Use of lipid disperse systems in transdermal drug delivery: Comparative study of flufenamic acid permeation among rat abdominal skin, silicon rubber membrane and stratum corneum sheet isolated from hamster cheek pouch

The characteristics of in vitro permeation of flufenamic acid (FA) from lipid disperse systems composed of phosphatidylcholine (PC) and glycosylceramide (GC) were compared among rat abdominal skin, a silicon rubber membrane (Silastic ®) and a stratum corneum (SC) sheet isolated from hamster cheek pouch. When a PC dispersion (PCD) containing 20 μmol PC/ml was applied, the permeation of FA through rat skin was enhanced approx. 2.2-fold compared with that from the lipid-free suspension (LFS). Further, a nearly 2-fold enhancement was observed when a GC-containing PCD (10% GC-PCD) was examined. A similar pattern of enhancement could be reproduced when cheek pouch SC was used instead of, rat skin, whereas it was not observed in Silastic ®. The enhanced permeation in the skin could not be explained on the basis of the incremental increase in the apparent solubilities. A significant correlation was observed between skin permeation and epidermal tissue uptake of FA from LFS and PCDs, although the nearly 2-fold increase found in 10% GC-PCD might be due to mechanisms other than the increase in epidermal tissue uptake. The usefulness of an SC sheet isolated from hamster cheek pouch, a new model membrane without appendages, in studying the direct action of either permeation enhancers or dosage forms designed to enhance the percutaneous permeation of drugs on the SC is discussed.