Natural surfactant-based topical vehicles for two model drugs: Influence of different lipophilic excipients on in vitro/in vivo skin performance

This study focuses on the properties of topical vehicles based on alkylpolyglucoside natural surfactant-mixed emulsifier, cetearyl glucoside and cetearyl alcohol, in order to propose their use as “ready to use” pharmaceutical bases for a number of model drugs. We were interested to investigate how the alternative use of three lipophilic excipients (Ph. Eur. 6.0), differing in their polarity indexes (medium chain triglycerides (MG), decyl oleate (DO), and isopropyl myristate (IPM), respectively), affects the colloidal structure of the alkylpolyglucoside-based vehicles and in vitro permeation profiles of two model drugs: diclofenac sodium (DC) and caffeine (CF), both sparingly soluble in water. Finally, we aimed to evaluate the safety profile of such vehicles in vitro (acute skin irritation test using a cytotoxicity assay), comparing it with in vivo data obtained by the methods of skin bioengineering.The results have shown that the emulsion vehicles consisted of a complex colloidal structure of lamellar liquid crystalline and lamellar gel crystalline type. Varying of lipophilic excipient influenced noteworthy variations in the colloidal structure demonstrated as different rheological profiles accompanied to the certain degree by different water distribution modes, but notably provoked by drug nature (an amphiphilic electrolyte drug vs. nonelectrolyte). In vitro permeation data obtained using ASC membranes in an infinite dose-type of experiment stressed the importance of the vehicle/solute interactions in case of small variation in formulation composition, asserting the drug properties in the first hours of permeation and rheological profile of the vehicles in the later phase of experiment as decisive factors. In vitro skin irritation test demonstrated a mild nature of the emulsifying wax and the absence of negative effects of used oil phases on cell viability in formulation concentrations correspondent to the therapeutic need. This result alongside with data obtained from in vivo study, could additionally promote investigated topical vehicles as prospective “ready to use” pharmaceutical bases.     

Vehicles based on a sugar surfactant: Colloidal structure and its impact on in vitro/in vivo hydrocortisone permeation

An emerging class of natural surfactants, named alkylpolyglucosides, which can form both, the thermotropic and the lyotropic liquid crystalline phases, were focused. The aim of the study was to integrate some physicochemical properties (characterised through the polarization and transmission electron microscopy, wide-angle X-ray diffraction, thermal analysis and rheology) of the three formulations based on cetearyl glucoside and cetearyl alcohol, with the in vitro (the artificial skin constructs) and in vivo bioavailability of hydrocortisone (HC), in comparison with a standard pharmacopoeial vehicle. The parameters measured in vivo were erythema index (an instrumental human skin blanching assay), transepidermal water loss (TEWL) and stratum corneum hydration. A complex colloidal structure of lamellar liquid crystalline and lamellar gel crystalline type was deduced for sugar surfactant-based vehicles. In dependence on surfactant/water/oil ratio, several thermodinamically variable fractions of water were predicted. Rheological profile of the vehicle appeared to influence the in vitro profile of permeation. A surplus of total amount of drug permeated in vitro from the alkylpolyglucoside-based vehicles coincided with the more pronounced increase of TEWL and less marked blanching action of HC from the selected alkylpolyglucoside-based vehicle tested in vivo, related to the pharmacopoeial one. These findings imply an enhanced delivery of HC from this vehicle and its putative penetration enhancing effect, probably dependent on specific distribution of the vehicle's inherent water.     

An alkylpolyglucoside surfactant as a prospective pharmaceutical excipient for topical formulations: The influence of oil polarity on the colloidal structure and hydrocortisone in vitro/in vivo permeation

There is a growing need for research into new skin- and environment-friendly surfactants. This paper focuses on a natural surfactant of an alkylpolyglucoside type, which can form both thermotropic and lyotropic liquid-crystalline phases. The aim of this study was to relate some physicochemical properties (characterised by polarisation and transmission electron microscopy, thermal analysis and rheology) of the three formulations based on cetearyl glucoside and cetearyl alcohol, to the results of in vitro and in vivo bioavailability of hydrocortisone (HC). The three formulations contained oils of different polarity (medium chain triglycerides: MG, isopropyl myristate: IPM and light liquid paraffin: LP), respectively. In vitro permeation was followed through the artificial skin constructs (ASC), while the parameters measured in vivo were erythema index: EI (using instrumental human skin blanching assay), transepidermal water loss (TEWL) and stratum corneum hydration (SCH). The vehicles based on cetearyl glucoside and cetearyl alcohol showed a complex colloidal structure of lamellar liquid-crystalline and lamellar gel-crystalline type, depending on oil polarity. Rheological profile of the vehicle was directly related to the in vitro profile of the HC permeation. In vivo results suggested that the vehicle with MG retarded the HC permeation, whereas less polar IPM and non-polar LP enhanced it. It is suggested that the enhancement is achieved either by a direct interaction with lipid lamellae of the SC or indirectly by improving skin hydration.

There were no adverse effects during in vivo study, which indicates a good safety profile of this alkylpolyglucoside surfactant.     

Effects of vehicles and enhancers on transdermal delivery of melatonin

For a more effective transdermal delivery of melatonin (MT), the effects of vehicles and enhancers on its skin permeation and lag time were evaluated. Skin permeation study was conducted in Franz diffusion cells using excised hairless mouse skins. MT was analyzed by HPLC. As vehicles, ethanol (EtOH), polyethylene glycol 400 (PEG), or propylene glycol (PG) was used alone or mixed with a phosphate buffer. Binary vehicles (EtOH/buffer, PEG/buffer, PG/buffer) showed different effects on the skin permeation of MT and its lag time. Compared with the buffer alone, the PEG/buffer shortened the lag time of MT but reduced its skin permeation. EtOH/buffer significantly increased the flux of MT but prolonged the lag time with the content of EtOH. PG/buffer did not affect the lag time but slightly increased the skin permeation of MT at the higher content of PG (> or =80%). These results indicate that the composition of vehicles exerts significant influence but it per se might have limitation in modulating the transdermal delivery of MT. Next, one tested whether fatty acids could more effectively enhance the skin permeation of MT and shorten its lag time. Given the influence of vehicles on both permeation and lag time, PG was used as a vehicle for fatty acids. The permeation-enhancing effects of saturated fatty acids increased in the following order: C10>C12>C14>C16>C18. The saturated fatty acid, however, did not significantly shorten the lag time regardless of the carbon chain length. Meanwhile, similar to saturated lauric acid (C12), unsaturated oleic acid (C18) dramatically enhanced the skin permeability coefficient of MT more than 950-fold over the effect of PG alone. Moreover, oleic acid showed the shortest lag time (2.1 h). The results suggest that oleic acid in a suitable vehicle could more effectively enhance the skin permeation of MT and shorten its lag time than did the vehicles of various compositions.     

Identification and assessment of permeability enhancing vehicles for transdermal delivery of glucosamine hydrochloride

As an initial step to develop the transdermal delivery system of glucosamine hydrochloride (GL-HCl), the permeation study across the rat skin in vitro was performed to identify the most efficient vehicle with regard to the ability to deliver GL-HCl transdermally. The GL-HCl formulations such as o/w cream, liposome suspension, liposomal gel, and liquid crystalline vehicles were prepared and compared for transdermal flux of GL-HCl. The liquid crystalline vehicles were more effective in increasing the skin permeation of GL-HCl than o/w cream and liposomal vehicles. Of the liquid crystalline vehicles tested, the permeation enhancing ability of the cubic phase was greater than that of the hexagonal phase when the nanoparticle dispersion was used. The skin permeation enhancing ability of the cubic nanoparticles for GL-HCl was further increased by employing both oleic acid and polyethylene glycol 200. Therefore, the cubic liquid crystalline nanodispersion containing oleic acid and PEG 200 can provide a possibility of clinical application of transdermal GL-HCl.     

不同基质和透皮促进剂对秋水仙碱凝胶剂体外透皮特性的影响

目的优选秋水仙碱凝胶剂基质和相应的透皮促进剂,为制备秋水仙碱透皮给药新制剂提供参考资料。方法采用改良的Franz扩散池法,并通过RP-HPLC法测定接收液中秋水仙碱的含量。结果3种基质的秋水仙碱凝胶体外透皮比率为Carbopol基质凝胶>HPMC基质凝胶>CMC-Na基质凝胶。以Carbopol为基质,加入几种透皮促进剂后,秋水仙碱凝胶的体外透皮速率为丙二醇>冰片>氮酮>薄荷油。结论凝胶剂作为秋水仙碱透皮吸收新剂型可行。     

Effect of vehicles and penetration enhancers on the in vitro percutaneous absorption of tenoxicam through hairless mouse skin

The effects of vehicles and penetration enhancers on the in vitro permeation of tenoxicam from saturated solutions through dorsal hairless mouse skin were investigated. Various types of vehicles, including ester-, alcohol-, and ether-types and their mixtures, were used as vehicles, and then a series of fatty acids and amines were employed as enhancers, respectively. Even though the fluxes of tenoxicam from saturated pure vehicles were generally low (0.1-1.1 microg/cm2 per h), the skin permeability of tenoxicam was significantly increased by the combination of diethylene glycol monoethyl ether (DGME) and propylene glycol monolaurate (PGML) or propylene glycol monocaprylate (PGMC); the highest fluxes were achieved at 40% of DGME in both of the two cosolvents. The marked synergistic enhancement was also obtained by using propylene glycol (PG)-oleyl alcohol (OAl) cosolvent. The greatest flux was attained by the addition of unsaturated fatty acids at 3% concentration to PG. But saturated fatty acids failed to show a significant enhancing effect. The enhancement factors with the addition of oleic acid (OA) or linoleic acid (LOA) to PG were 348 and 238, respectively. Tromethamine (TM) showed an enhancing effect by the increased solubility; however, triethanolamine (TEA) did not show a significant enhancing effect. Rather, it decreased the fluxes of tenoxicam when added to PG with fatty acids. The above results indicate that the combinations of lipophilic vehicles like OA, LOA or OAl and hydrophilic vehicles like PG can be used for enhancing the skin permeation of tenoxicam.     

Impact of Different Vehicles for Laser-Assisted Drug Permeation via Skin: Full-Surface versus Fractional Ablation

Purpose

This study aimed to assess impact of different vehicles for laser-assisted skin drug delivery. We also tried to uncover the mechanisms by which different vehicles affect laser-aided skin permeation.

Methods

Full-surface ablative (conventional) and fractional lasers were used to irradiate nude mouse skin. Imiquimod and 5-aminolevulinic acid (ALA) were used as lipophilic and hydrophilic permeants. Vehicles employed included water with 40% polyethylene glycol 400 (PEG 400), propylene glycol (PG), and ethanol. Lipid nanoparticles were also utilized as carriers.

Results

In vitro permeation profiles showed improvement in imiquimod flux with conventional laser (2.5 J/cm²) producing a 12-, 9-, and 5-fold increase when loading imiquimod in 40% PEG400, PG, and ethanol, respectively, as compared with intact skin. Nanoparticulate delivery by laser produced a 6-fold enhancement in permeation. Fractional laser produced less enhancement of imiquimod delivery than conventional laser. Laser exposure increased follicular imiquimod accumulation from 0.80 to 5.81 μg/cm². ALA permeation from aqueous buffer, PEG 400, and PG with conventional laser treatment was 641-, 445-, and 104-fold superior to passive control. In vivo skin deposition of topically applied ALA examined by confocal microscopy indicated the same trend as the in vitro experiment, with aqueous buffer showing the greatest proporphyllin IX signaling. Diffusion of cosolvent molecules into ablated skin and drug partitioning from vehicle to skin are two predominant factors controlling laser-assisted delivery. In contrast to conventional laser, lateral drug diffusion was anticipated for fractional laser.

Conclusions

Our results suggest that different drug delivery vehicles substantially influence drug penetration enhanced by lasers.     

Release characteristics of anionic drug compounds from liquid crystalline gels I: Passive release across non-rate-limiting membranes

Liquid crystalline gels (LCG) offer the formulator dynamic and flexible vehicles, into which actives, enhancers and other adjuvants with a wide range of physicochemical properties can be incorporated. This is achievable because of the biphasic oil/water composition of the gel. In this paper, the suitability of an isotropic liquid crystalline gel is investigated for a range of anionic drug molecules, with particular emphasis on sodium diclofenac. Parameters, which have been investigated, include the mode of vehicle preparation, the effect of the concentration of the drug and how buffering the gel and/or the receptor medium affect the release profiles. Such profiles have been measured for the sodium salts of benzoate, salicylate and indomethacin. The passive release from the standard system was found to adhere to matrix-controlled diffusion. An increase in concentration leads to a non-linear increase in the cumulative release of sodium diclofenac from the gels. In direct contrast to the result reported for cationic salbutamol base, optimum release from the gel was achieved when neither the receptor medium nor the aqueous phase of the gel was buffered. The percentages released of the sodium salts of benzoate, salicylate and indomethacin, after 24 h, were determined to be 25, 26 and 19%, respectively, and these are significantly greater than the release of sodium diclofenac. This suggests that diclofenac undergoes ion-pairing or complexation within the gel, which inhibits its diffusion from the vehicle. Future papers will report on the incorporation of enhancers and the effects of iontophoresis on the release profiles of drugs from these gels, and ultimately on the transdermal transport of drugs from these vehicles across human and porcine skin.     

In vitro percutaneous penetration of acyclovir from solvent systems and Carbopol 971-P hydrogels: influence of propylene glycol

The mechanism underlying propylene glycol (PG) effects on acyclovir (ACV) penetration through human epidermis were studied. Solvent systems and Carbopol gels containing increasing percentage of PG (from 0% to 70%, w/w) were used. Viscosity studies of both vehicles were carried out to characterise the influence of rheological behaviour. In solvent systems skin permeation values of ACV increase as the concentration of PG increase yielding a maximum enhancement ratio (ER = 10) for 70% PG. The release rate of ACV from gels was determined. Higuchi's model was used to estimate the apparent diffusion coefficient of the drug. These values show a decrease as the content of PG in the vehicle increases; this effect could be attributed to the increase of the viscosity in the diffusional pathway. When gels are used skin permeation values of ACV were smaller than those of the solvent systems. This could be attributed to the network structure created by the polymer that increases the length of the diffusional pathway. The maximum ER (= 6.8) was for Carbopol gel containing 50% PG. Therefore, these gels can be considered candidates for further research to confirm their usefulness as delivery systems for ACV topical formulations.     

Solubility and transdermal permeation properties of a dehydroepiandrosterone cyclodextrin complex from hydrophilic and lipophilic vehicles

The permeation ability of a compound is due principally to its concentration in the vehicle and to its aptitude to cross the stratum corneum of the skin. In this work ex-vivo permeation studies on newly developed formulations containing dehydroepiandrosterone (DHEA) were carried out to investigate vehicles that increase drug permeation through the skin. To enhance the solubility of DHEA, its complex form with alpha-cyclodextrin was used. In addition, the two forms (pure drug and complex form) were introduced in hydrophilic (water), lipophilic (paraffin oil), and microemulsion vehicles to evaluate the synergic effect of cyclodextrins and microemulsion vehicles on solubility and permeation. From the results, DHEA solubility is notably conditioned by the type of the vehicle used: the highest solubilities (both for pure and complex drug forms) were obtained with microemulsion, followed by paraffin oil and water. Moreover, in all the studied vehicles, the c-DHEA was more soluble than DHEA. Permeation profile fluxes showed very interesting differences. That reflect the varying drug forms (pure drug and complex form), vehicles used, and drug concentrations in the vehicles. The major flux was obtained in complex of DHEA with alpha-cyclodextrins in the microemulsion vehicle. Therefore, this type of vehicle and drug form would be very useful in the development of a topical formulation containing DHEA.     

Film drying and complexation effects in the simultaneous skin permeation of ketoprofen and propylene glycol from simple gel formulations

This work investigated the simultaneous permeation of ketoprofen and propylene glycol (PG) across pig ear skin from simple gel formulations administered under simulated in-use conditions. The aims were to quantify rates of permeation of both solvent and active, probe the effects of formulation drying and gain insight into drag/complexation interactions. Simple 3-component gels were formulated using a fixed amount of ketoprofen and hydroxypropyl cellulose thickener with decreasing content of solvent propylene glycol. Multiple finite (5 mg x 15 mg) doses were massaged over 24h into full thickness pig ear skin in vertical Franz-type diffusion cells. The permeation of ketoprofen was inversely proportional to the content of PG, whereas the permeation of PG was directly proportional, although the amount of PG permeated was always greater than ketoprofen, even from the driest gel practically achievable. In this state, the molar ratio of PG/ketoprofen was approximately 12, suggesting that this number of PG molecules constitutes the solvation cage of ketoprofen. Dragging/pulling effect extends throughout the skin and into the receptor compartment and probably the system, in an in vivo situation. Although PG may represent a worse case scenario given its well-documented skin permeation enhancement properties, it is probable that other solvents exert a similar effect on solutes across skin. A drying film will behave in different ways depending on the nature of both the thickener and solvent, where the outcomes are not readily predictable. It is important to account for the fate of all species administered from a topical formulation.     

DEET-loaded solid lipid particles for skin delivery: in vitro release and skin permeation characteristics in different vehicles

DEET (N,N-diethyl m-toluamide) is a lipophilic compound which has a common use as an insect repellent and causes not only skin irritation but also systemic side effects at high concentrations in long-term skin application. In this study, DEET is incorporated into solid lipid particles, a colloidal drug delivery system, in order to reduce the percutaneous permeation and avoid toxic effects and also maintain drug effectiveness on the skin surface for a long duration of insect repellence. Solid lipid particles were prepared based on emulsion systems at different concentrations and after the characterization studies, the formulation with 20% lipid phase and 1:1 drug:lipid ratio was carried to in vitro release and skin permeation studies. Solid lipid particles with DEET were compared to free DEET using cream and hydrophilic gel vehicles. Results showed that incorporation of DEET into solid lipid particles reduced the release rate and skin permeation of DEET. Imaging studies using scanning electron microscopy showed that there were still solid lipid particles on skin surface after 2 h indicating that DEET could be present for a longer time on the application site.     

Transdermal delivery of nicardipine: an approach to in vitro permeation enhancement

Nicardipine hydrochloride (NC-HCl), a calcium channel blocker for the treatment of chronic stable angina and hypertension, seems to be a potential therapeutic transdermal system candidate, mainly due to its low dose, short half-life, and high first-pass metabolism. The objective of the present study was to evaluate its flux and elucidate mechanistic effects of formulation components on transdermal permeation of the drug through the skin. Solubility of NC-HCl in different solvent systems was determined using a validated HPLC method. The solubility of drug in various solvent systems was found to be in decreasing order as propylene glycol (PG)/oleic acid (OA)/dimethyl isosorbide (DMI) (80:10:10 v/v) > PG > PG/OA (90:10 v/v) > polyethylene glycol 300 > ethanol/PG (70:30 w/w) > transcutol > dimethyl isosorbide (DMI) > ethanol > water and buffer 4.7 > 2-propanol. Propylene glycol was then selected as the main vehicle in the development of a transdermal product. As a preliminary step to develop a transdermal delivery system, vehicle effect on the percutaneous absorption of NC-HCl was determined using the excised skin of a hairless guinea pig. Vehicles investigated included pure solvents alone and their selected blends, chosen based on the solubility results. In vitro permeation data were collected at 37 degrees C, using Franz diffusion cells. The skin permeation was then evaluated by measuring the steady state permeation rate (flux) of NC-HCl, lag time, and the permeability constant. The results showed that no individual solvent was capable of promoting NC-HCl penetration. Permeation profiles of the drug through hairless guinea pig skin using saturated solutions of drug were constructed. Among the systems studied, the ternary mixture of PG/OA/DMI and binary mixture of PG/OA showed excellent flux. The flux value of the ternary system was nearly three times higher than the corresponding values obtained for the binary solvent. A similar trend also was observed for the permeation constant, while the values of lag time were reversed. The ternary mixture was then selected as a potential absorption enhancement vehicle for the transdermal delivery of drug. In general, higher fluxes were observed through hairless guinea pig skin as compared with the human stratum corneum. Based on the results obtained from the release study of NC-HCl from saturated solutions of the drug, a novel lecithin organogel (microemulsion-based gel) composed of soybean lecithin, propylene glycol, oleic acid, dimethyl isosorbide, and isopropyl myristate was developed as a possible matrix for transdermal delivery of NC-HCl. In vitro percutaneous penetration studies from this newly developed gel system through giunea pig skin and human stratum corneum revealed that the organogel system has skin-enhancing potential and could be a promising matrix for the transdermal delivery of nicardipine. Furthermore, higher permeation rates were observed when nicardipine free base was incorporated into the gel matrix instead of hydrochloride salt.     

Does lactobionic acid affect the colloidal structure and skin moisturizing potential of the alkyl polyglucoside-based emulsion systems?

Moisturizing creams are the most prescribed products in dermatology, essential in maintaining healthy skin as well as in the topical treatment of some diseases. The irritation potential of commonly used emulsifiers and moisturizing ingredients, but also their mutual interactions, could affect the functionality and safety of those dermopharmaceutics. The aim of this study was to promote moisturizing alkyl polyglucoside (APG)-based emulsion as vehicle for lactobionic acid (LA), advantageous representative of the alphahydroxyacids (AHAs)-multifunctional moisturizers, assessing the safety for use (in vitro acute skin irritation test using cytotoxicity assay compared with in vivo data obtained using skin bioengineering methods) and in vivo moisturizing capacity (bioengineering of the skin). In order to investigate possible interactions between APG mild natural emulsifier-based emulsion and LA, a deeper insight into the colloidal structure of the placebo and the emulsion with LA was given using polarization and transmission electron microscopy, rheology, thermal and texture analysis. This study showed that APG-based emulsions could be promoted as safe cosmetic/dermopharmaceutical vehicles and carriers for extremely acidic and hygroscopic AHA class of actives (specifically LA); prospective safety for human use of both APG and LA with the correlation between in vivo and in vitro findings was shown. However, it was revealed that LA strongly influenced the colloidal structure of the emulsion based on APGs and promoted the formation of lamellar structures which reflects onto the mode of water distribution within the cream. The advantageous skin hydrating potential of LA-containing emulsion vs. placebo was unlikely to be achieved, pointing that emulsions stabilized by lamellar liquid crystalline structures probably are not satisfying carriers for highly hygroscopic actives in order to reach the full moisturizing potential. Safe and effective use on dry skin is presumed.     

Examination of liquid crystalline gel systems containing chlorhexidine on the structure and the drug release

The aim of the thesis was to examine liquid crystalline gel systems as novel, locally applied drug delivery systems. For developing liquid crystalline vehicle, different ratio of Synperonic A7--water mixtures was prepared. Chlorhexidine, chlorhexidine acetate and chlorhexidine gluconate were used as model drugs. Liquid crystalline structure, drug release and drug release kinetic of the samples were studied at increasing surfactant concentration and the effect of the different drugs on the physicochemical properties of the samples and on the membrane transport was examined. For the analysis of the prepared liquid crystalline systems polarising microscopy, rheology test, differential scanning calorimetry, small-angle neutron scattering and transmission electron microscopy were carried out. The drug release and membrane transport experiments were performed by Franz type vertical diffusion cell and Sartorius Resorptionsmodell apparatus. According to our results liquid crystalline vehicles of lamellar and hexagonal structure formed by increasing the surfactant concentration. The drug release studies indicated, that the kinetic of the release strongly depend on the liquid crystalline structure, zero order release occurs from hexagonal structures and anomalous transport occurs from lamellar structures. The addition of chlorhexidine species to the systems modified the structure of the liquid crystalline system. As a results of liquid crystal-drug interaction the solubility of chlorhexidine base and its diffusion through lipophilic membranes increased in comparison with those of the chlorhexidine salts.     

Dermal Peptide Delivery Using Enhancer Molecules and Colloidal Carrier Systems - Part I: Carnosine

Due to the lipophilic properties of the uppermost skin layer of the stratum corneum (SC), it is highly challenging to attain therapeutic concentrations of active substances; hydrophilic drugs, in particular, penetrate poorly. The purpose of this study was the improvement of the topical bioavailability of the hydrophilic dipeptides L-carnosine and its related compound N-acetyl-L-carnosine. Different strategies were investigated. On the one hand, an enhancer molecule, 1,2-pentylene glycol (PG), was added to a standard preparation, and on the other hand, a microemulsion (ME-PG) system was developed. Both were compared to the standard formulation without an enhancer molecule. For all 3 preparations, the penetration of the peptides in ex vivo human skin was investigated. This allows statements to be made regarding dermal penetration, localization and distribution of the active substances in each skin layer as well as the influence of vehicle variations, in this case, the addition of PG or the incorporation of N-acetyl-L-carnosine in an ME-PG system. For L-carnosine and N-acetyl-L-carnosine, the use of the standard preparation with PG resulted in a significant increase of the substance within the SC. Approximately 6-fold and higher dipeptide concentrations in the SC and in the viable skin layers were detected at all experimental periods compared to the formulation without the enhancer molecule and the ME-PG. High concentrations of the compounds were found after a short period of time in the viable skin layers after applying the enhancer molecule, even in concentrations of 5%. The application of the colloidal carrier system did not lead to a higher penetration rate of N-acetyl-L-carnosine in comparison to both standard preparations, although it must be said that the microstructure of the investigated ME-PG might not have been optimal for the hydrophilic properties of the dipeptide.     

Liquid crystalline Pluronic 105 pharmacogels as drug delivery systems: preparation,characterization, and in vitro transdermal release

In this study, we report the results of our investigations on the percutaneous permeation profiles of Diclofenac sodium, Paracetamol, Propanolol hydrochloride, and α-Tocopherol from the different lyotropic liquid crystalline phases obtained by Pluronic P105/water mixtures, in order to understand if the particular assembly shown in the formulations could influence the delivery across the skin.

Recent studies have focused on the Pluronic liquid crystalline phases to evaluate the potential use of these phases in drug delivery, but no comparative investigation has been yet performed on the drug permeation from the different liquid crystalline phases obtained by the same Pluronic surfactant.

The cubic, hexagonal, and lamellar mesophases (loading the above-mentioned drug) were characterized by Deuterium Nuclear Magnetic Resonance spectroscopy and Polarized Optical Microscopy observations. Results revealed that the liquid crystalline gel microscopic structure obtained in the different formulations drastically affects the drug percutaneous availability. As a consequence these systems could be proposed as novel transdermal drug delivery systems.     

Microemulsions as colloidal vehicle systems for dermal drug delivery. Part V: Microemulsions without and with glycolipid as penetration enhancer

The aim of this study was to investigate the dermal administration of a highly hydrophilic model drug, diphenhydramine (DPH), in colloidal systems with an aqueous colloidal phase in the presence of a glycolipid (GL) as a penetration modifier. Dermal penetration of DPH, GL, and isopropylpalmitate (IPP) from ME systems without GL and with GL as well as from a hydrogel used as standard formulation were estimated in vitro using human skin. The penetration of the drug, the oil (IPP), and the GL was measured with highly sensitive HPLC, HPLC-MS, and GC-MS assays, respectively. It could be shown that penetration modifier GL is penetrating very fast, and to a high extent into and through the human skin. In contrast, the penetration of IPP used as oily phase in the ME is limited. When incorporated in the ME systems GL and DPH was accumulated in the viable epidermis and in the dermis. Using ME containing a penetration modifier such as GL, a slight additional enhancing effect could be observed, particularly concerning the penetration of DPH into the acceptor fluid when a highly hydrophilic drug such as DPH was applied.     

Effects of vehicles and enhancers on transdermal delivery of clebopride

The effects of vehicles and penetration enhancers on the skin permeation of clebopride were evaluated using Franz type diffusion cells fitted with excised rat dorsal skins. The binary vehicle system, diethylene glycol monoethyl ether/isopropyl myristate (40/60, w/w), significantly enhanced the skin permeation rate of clebopride. The skin permeation enhancers, oleic acid and ethanol when used in the binary vehicle system, resulted in relatively high clebopride skin permeation rates. A gel formulation consisting of 1.5% (w/w) clebopride, 5% (w/w) oleic acid, and 7% (w/w) gelling agent with the binary vehicle system resulted in a permeation rate of 28.90 microg/cm2/h. Overall, these results highlight the potential of clebopride formulation for the transdermal route.