Ethosomes-based topical delivery system of antihistaminic drug for treatment of skin allergies

Abstract

Cetirizine is indicated for the treatment of allergic conditions such as insect bites and stings, atopic and contact dermatitis, eczema, urticaria. This investigation deals with development of a novel ethosome-based topical formulation of cetirizine dihydrochloride for effective delivery. The optimised formulation consisting of drug, phospholipon 90 G? and ethanol was characterised for drug content, entrapment efficiency, pH, vesicular size, spreadability and rheological behaviour. The ex vivo permeation studies through mice skin showed highest permeation flux (16.300?±?0.300?µg/h/cm²) and skin retention (20.686?±?0.517?µg/cm²) for cetirizine-loaded ethosomal vesicles as compared to conventional formulations. The in vivo pharmacodynamic evaluation of optimised formulation was assessed against oxazolone-induced atopic dermatitis (AD) in mice. The parameters evaluated were reduction in scratching score, erythema score, skin hyperplasia and dermal eosinophil count. Our results suggest that ethosomes are effective carriers for dermal delivery of antihistaminic drug, cetirizine, for the treatment of AD.     

Controlled delivery of ropinirole hydrochloride through skin using modulated iontophoresis and microneedles

Abstract

The objective of this study was to investigate the effect of modulated current application using iontophoresis- and microneedle-mediated delivery on transdermal permeation of ropinirole hydrochloride. AdminPatch® microneedles and microchannels formed by them were characterized by scanning electron microscopy, dye staining and confocal microscopy. In vitro permeation studies were carried out using Franz diffusion cells, and skin extraction was used to quantify drug in underlying skin. Effect of microneedle pore density and ions in donor formulation was studied. Active enhancement techniques, continuous iontophoresis (74.13?±?2.20?µg/cm²) and microneedles (66.97?±?10.39?µg/cm²), significantly increased the permeation of drug with respect to passive delivery (8.25?±?2.41?µg/cm²). Modulated iontophoresis could control the amount of drug delivered at a given time point with the highest flux being 5.12?±?1.70?µg/cm²/h (5–7?h) and 5.99?±?0.81?µg/cm²/h (20–22?h). Combination of modulated iontophoresis and microneedles (46.50?±?6.46?µg/cm²) showed significantly higher delivery of ropinirole hydrochloride compared to modulated iontophoresis alone (84.91?±?9.21?µg/cm²). Modulated iontophoresis can help in maintaining precise control over ropinirole hydrochloride delivery for dose titration in Parkinson’s disease therapy and deliver therapeutic amounts over a suitable patch area and time.     

High-efficient nano-carrier gel systems for testosterone propionate skin delivery

Abstract

The purpose of the current investigation was to evaluate the skin delivery potential of the different nano-carrier gels including liposomal gel, ethosomal gel and microemulsion gel bearing testosterone propionate (TP) as a testosterone deficient therapy. The prepared nano-particles were characterized for their shape, particle size distribution and zeta potential. In vitro skin permeation and in vivo transdermal delivery of nano-carrier gels were studied with the Franz diffusion cells and confocal laser scanning microscopy (CLSM). The results showed that all of nano-particles were almost spherical with low polydispersity and nano-metric size range from 40 to 200?nm. TP ethosomal gel also provided an enhanced transdermal flux of 7.64?±?1.4?μg/cm²/h and a decreased lag time of 0.69?h across rat skin as compared with the other two formulations. The skin penetration efficiency of TP nano-carrier gels also revealed that TP ethosomal gel would enhanced penetration of rhodamine red (RR)-loaded formulation to the deeper layers of the skin (268?µm) than the liposomal gel (192?µm) and microemulsion gel (228?µm). This study demonstrated TP ethosomal gel is a promising nano-carrier for delivering TP through 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.     

Synergic enhancing-effect of DEET and dodecylamine on the skin permeation of testosterone from a matrix-type transdermal delivery system

The synergic in vitro skin permeation enhancing-effect of N,N-diethyl-m-toluamide (DEET) and dodecylamine was investigated in order to develop a novel non-scrotal matrix-type transdermal delivery system of testosterone (TS). When DEET was loaded in DuroTak^® 87-2510 together with 2% TS and 3% dodecylamine, the in vitro rat skin permeation rate of TS synergistically increased as DEET concentration increased up to 0.5%. No further increase in permeation was observed thereafter and a plateau was observed up to 3.8% DEET. Moreover, compared to 0.5% DEET concentration, the addition of 3.8% of DEET in combination with 3% dodecylamine and 6% TS further increased the permeation rate of TS, and the maximum permeation rate of 11.21 μg/cm²/h was achieved. The in vitro skin permeation rates of TS from a transdermal delivery system of DuroTak^® 87-2510 containing 6% TS, 3% dodecyamine, and 3.8% DEET were in the following order: hairless mouse skin > rat skin > human cadaver skin. Assuming that a system with a surface area of 60 cm² is applied, the human cadaver skin permeation rate of 5.74 μg/cm²/h achieved in this study can be interpreted as being equivalent to delivering ～ 8.?27?mg of TS per day. Considering that the commercially available product (Testoderm^®TTS) for non-scrotal skin of the same surface area is designed to administer 5?mg of TS per day, the new formulation could maintain therapeutic plasma concentration of TS at a smaller surface area of 40 cm².     

Skin Permeation Enhancement in Aqueous Solution: Correlation With Equilibrium Enhancer Concentration and Octanol/Water Partition Coefficient

The effectiveness of skin penetration enhancers and the enhancer concentration required for effective skin permeation enhancement are difficult to predict. A comprehensive quantitative structure-enhancement relationship of chemical penetration enhancers for skin permeation is not currently available. The present study (a) investigated the relationship between skin permeation enhancement and chemical enhancer concentration and (b) examined a simple quantitative structure-enhancement relationship for predicting skin permeation enhancement to guide enhancer formulation development. In the present analysis, data from previous skin permeation studies that used the symmetric/equilibrium configuration and skin parallel pathway model were summarized to determine the relationship between enhancement factor and enhancer concentration. Under the equilibrium conditions, semilogarithmic linear relationships between enhancement factor (E) and enhancer aqueous concentration (C) were observed and an enhancer potency parameter (α) was defined. A correlation between the potency parameter α and enhancer octanol/water partition coefficient (Koct) was obtained. The enhancement factor relationship was derived: Log E = 0.32 ? C ? Koct. The results suggest that a “threshold” of (C ? Koct) > 0.5 M is required to induce effective skin permeation enhancement under these conditions. Consistent with the analyses in previous studies, the data suggest that octanol represents the skin barrier microenvironment for the penetration enhancers.     

Feasibility of Proniosomes-Based Transdermal Delivery of Frusemide: Formulation Optimization and Pharmacotechnical Evaluation

The aim of the present study was to formulate non-ionic surfactant vesicles of frusemide to enhance its skin permeation and to develop a transdermal therapeutic system using provesicular approach. The effect of various formulation variables on the transdermal flux, amount of drug deposited in skin, and plasma level of drug were studied. The skin permeation studies were conducted on rat skin and human skin for quantification of permeation parameters. With PGS3 formulation [Span 40:soyalecithin:cholesterol (4.5:4.5:1)], the plasma level in the rats had reached to a level of 0.42 ± 0.13 µg/mL at the sampling interval of 4 hr and remained within the therapeutic concentration range (1.66–0.3 µg/mL) for the next 12 hr. Results showed that proniosomal formulation was able to sustain the drug level in the blood and offer a promising means for non-invasive delivery of frusemide.     

Novel carbopol-based transfersomal gel of 5-fluorouracil for skin cancer treatment: in vitro characterization and in vivo study

Abstract

5-fluorouracil (5-Fu) is an antineoplastic drug, topically used for the treatment of actinic keratosis and nonmelanoma skin cancer. It shows poor percutaneous permeation through the conventionally applicable creams and thus inefficient for the treatment of deep-seated skin cancer. In the present article, transfersomal gel containing 5-Fu was investigated for the treatment of skin cancer. Different formulation of tranfersomes was prepared using Tween-80 and Span-80 as edge activators. The vesicles were characterized for particle size, shape, entrapment efficiency, deformability and in vitro skin permeation. Optimized formulation was incorporated into 1% carbopol 940 gel and evaluated for efficacy in the treatment of skin cancer. 5-Fu-loaded transfersomes (TT-2) has the size of 266.9?±?2.04?nm with 69.2?±?0.98% entrapment efficiency and highest deformability index of 27.8?±?1.08. Formulation TT-2 showed maximum skin deposition (81.3%) and comparable transdermal flux of 21.46?µg/cm²?h. The TT-2-loaded gel showed better skin penetration and skin deposition of the drug than the marketed formulation. Composition of the transfersomal gel has been proved nonirritant to the skin. We concluded that the developed 5-Fu-loaded transfersomal gel improves the skin absorption of 5-Fu and provide a better treatment for skin cancer.     

Formulation,in vitro,and in vivo evaluation of matrix-type transdermal patches containing olanzapine

Transdermal patches of olanzapine were aimed to be prepared to overcome the side effects by oral application. The strategy was formulation of eudragit-based polymeric films to prepare transdermal patches by using nonionic (span-20), anionic (sodium lauryl sulfate), cationic surfactant (benzalkonium chloride), and vegetable oil (olive oil) as permeation enhancers. The patches were subjected to physicochemical, in vitro release and ex vivo permeation studies. On the basis of in vitro release performance, ERL 100:ERS 100 in the ratio of 3:2 was selected for incorporation of permeation enhancers. The permeation studies showed that formulation containing 10% span 20 (OD3) exhibited greatest cumulative amount of drug permeated (19.02?±?0.21?mg) in 72?h, so OD3 was concluded as optimized formulation and assessed for pharmacokinetic, pharmacodynamic, and skin irritation potential. In vivo studies of optimized olanzapine patch in rabbit model revealed prolongation of action with F_rel 116.09% during 72-h study period. Neuroleptic efficacy of transdermal patch was comparable to oral formulation during rotarod and grip test in Wistar albino rats with no skin irritation. Thus, developed formulation of olanzapine is expected to improve the patient compliance, form better dosage regimen, and provide maintenance therapy to psychotic patients.     

Pretreatment with Skin Permeability Enhancers: Importance of Duration and Composition on the Delivery of Diclofenac Sodium

The use of chemical penetration enhancers (CPEs) is one of the most common approaches to improve the dermal and transdermal delivery of drugs. However, often, incorporation of CPEs in the formulation poses compatibility and stability challenges. Moreover, incorporation of enhancers in the formulation leads to prolonged exposure to skin increasing the concern of causing skin reactions. This study was undertaken to assess whether pretreatment with CPEs is a rational approach to enhance the permeation of diclofenac sodium. In vitro experiments were performed across porcine epidermis pretreated with propylene glycol or oleic acid or their combinations for 0.5, 2, and 4 h, respectively. Pretreatment with combination of oleic acid in propylene glycol was found to enhance the permeation of diclofenac sodium significantly only at 10% and 20% (v/v) level, and only when the pretreatment duration was 0.5 h. Longer durations of pretreatment and higher concentration of oleic acid in propylene glycol did not enhance the permeation of diclofenac sodium. In vivo dermatokinetic studies were carried out on Sprague–Dawley rats. A twofold increase in AUC and C_max was observed in case of rats pretreated with enhancers over the group that was pretreated with buffer. In conclusion, this study showed that composition of the enhancers and duration of pretreatment are crucial in determining the efficacy of CPEs. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association.     

Effect of penetration enhancers on the release and skin permeation of bupranolol from reservoir-type transdermal delivery systems

A reservoir-type transdermal delivery system (TDS) of bupranolol (BPL) was designed and evaluated for different formulation variables like gel reservoirs (made with anionic and nonionic polymers), rate controlling membranes and penetration enhancers on the drug release and in vitro skin permeation kinetics of the devices. Keshary-Chien type diffusion cells and pH 7.4 phosphate buffered saline (PBS) were used for drug release studies and excised rat skin was used as a barrier for permeation experiments. The release rate of BPL from nonionic polymer gel reservoirs [hydroxypropyl methyl cellulose (HPMC), hydroxypropyl cellulose (HPC)] was much higher than anionic polymer gel reservoirs [carboxymethyl cellulose (CMC), sodium carboxymethyl cellulose (Na CMC) and sodium alginate)]. Among different rate controlling membranes, Cotran-polyethylene microporous membrane demonstrated highest release rate for BPL than all other membranes. An optimized TDS formulation with HPC gel and Cotran-polyethylene microporous membrane was used to study the effect of penetration enhancers on the release and skin permeation rate of BPL from the TDS. Permeation rates of the devices containing 5% (w/v) pyrrolidone (PY) or 1-methyl-2-pyrrolidone (MPY) were about 3- and 1.5-fold higher than control (no enhancer, P<0.01) indicating PY to be better penetration enhancer for BPL than MPY. The permeation rates of devices containing partially methylated beta-cyclodextrin (PMbetaCD) and PMbetaCD-BPL complex were about 2.5- and 1.4-fold higher than control (P<0.01). Inclusion of 10 and 30% w/v propylene glycol (PG) in the devices increased the permeation rate by 1.4- and 1.8-fold higher than control (P<0.05). In conclusion, reservoir-type TDS of BPL was developed and penetration enhancers increased the skin permeation of BPL at 4-5 times higher levels than the desired target delivery rate.     

Lidocaine carboxymethylcellulose with gelatine co-polymer hydrogel delivery by combined microneedle and ultrasound

Abstract

A study that combines microneedles (MNs) and sonophoresis pre-treatment was explored to determine their combined effects on percutaneous delivery of lidocaine from a polymeric hydrogel formulation. Varying ratios of carboxymethylcellulose and gelatine (NaCMC/gel ranges 1:1.60–1:2.66) loaded with lidocaine were prepared and characterized for zeta potential and particle size. Additionally, variations in the formulation drying techniques were explored during the formulation stage. Ex vivo permeation studies using Franz diffusion cells measured lidocaine permeation through porcine skin after pre-treatment with stainless steel MNs and 20?kHz sonophoresis for 5-and 10-min durations. A stable formulation was related to a lower gelatine mass ratio because of smaller mean particle sizes and high zeta potential. Lidocaine permeability in skin revealed some increases in permeability from combined MN and ultrasound pre-treatment studies. Furthermore, up to 4.8-fold increase in the combined application was observed compared with separate pre-treatments after 30?min. Sonophoresis pre-treatment alone showed insignificant enhancement in lidocaine permeation during the initial 2?h period. MN application increased permeability at a time of 0.5?h for up to ～17 fold with an average up to 4 fold. The time required to reach therapeutic levels of lidocaine was decreased to less than 7?min. Overall, the attempted approach promises to be a viable alternative to conventional lidocaine delivery methods involving painful injections by hypodermic needles. The mass transfer effects were fairly enhanced and the lowest amount of lidocaine in skin was 99.7% of the delivered amount at a time of 3?h for lidocaine NaCMC/GEL 1:2.66 after low-frequency sonophoresis and MN treatment.     

A combined approach of chemical enhancers and sonophoresis for the transdermal delivery of tizanidine hydrochloride

The effects of chemical enhancers and sonophoresis on the transdermal permeation of tizanidine hydrochloride (TIZ) across mouse skin were investigated. Parameters including drug solubility, apparent partition coefficient (APC), drug permeation, and degradation in skin were determined. Low frequency ultrasound was also applied in the presence and absence of chemical enhancers to assess whether drug permeation improved. APC values indicated that TIZ preferentially partitions into intercellular spaces and does not form a reservoir, with the drug also exhibiting good enzymatic stability in skin. Most of the enhancers studied significantly increased the permeation rate of TIZ through full thickness mouse skin in comparison with TIZ formulated in phosphate buffer. Maximum enhancement was observed for TIZ formulated as a suspension in 50% v/v aqueous ethanol containing 5% v/v citral. Sonophoresis significantly (p < 0.05) increased the cumulative amount of TIZ permeating through the skin at 15 and 30 min in comparison to passive diffusion. A synergistic effect was noted when sonophoresis was applied in the presence of chemical enhancers. The results suggest that the formulation of TIZ with an appropriate penetration enhancer may be useful in the development of a therapeutic system to deliver TIZ across the skin for a prolonged period, i.e. 24 hr. The application of ultrasound in association with chemical enhancers, such as the combination of 5% v/v citral in 50% v/v aqueous ethanol, could further serve as a non-oral and non-invasive drug delivery modality for the immediate therapeutic effect of muscle relaxants such as TIZ.     

Employing photoacoustic spectroscopy in the evaluation of the skin permeation profile of emulsion containing antioxidant phenolic-rich extract of Melochia arenosa

Context: Oxidative stress is an important factor modulating skin alterations. Melochia arenosa Benth. (Malvaceae) is a Brazilian plant with antimicrobial activity and antioxidant potential.

Objective: The objective of this study is to develop a topical formulation containing antioxidant phenolic-rich extract of M. arenosa and to evaluate its skin permeation profile.

Materials and methods: Response surface methodology was used to maximize the total phenolic (TP) content of the extract and its antioxidant activity was evaluated by 2,2-diphenyl-1-picryl-hydrazyl (DPPH), 2,2′-azinobis (3-ethylbenzothiazoline-6-sulfonic acid) (ABTS), and respiratory burst methods. An emulsion containing 1% optimized extract (OE) was developed and employed photoacoustic spectroscopy (PAS) for the determination of its skin permeation profile. The morphology of the skin was studied in histological sections stained with hematoxylin–eosin.

Results and discussion: The optimum conditions predicted for the major extractive efficiency of the phenolics with 100% ethanol led extraction time 101?h and plant:solvent proportion 1:13.5 (w/v). OE presented TP?=?724.6?±?8.2?mg GAE/g extract and scavenging capacity of DPPH (IC₅₀ value?=?11.43?±?0.14?µg/mL) and ABTS radicals (IC₅₀ value?=?35.42?±?0.48?µg/mL). The production of ROS by neutrophils after stimulation with phorbol miristate acetate was lower when the OE was present in the reaction medium, endorsing its high antioxidant capacity. The data obtained by PAS indicated that the OE present in the emulsion has permeated and was distributed in the whole skin. No histopathological alterations were observed in the histological analysis.

Conclusion: The formulation developed is a promising tool for skin care and could prevent the damage caused by oxidative stress.     

微针经皮给药系统应用于皮肤肿瘤治疗的研究进展

经皮给药系统（TDDS）作为一种经表皮给药途径递药,近年来受到广泛关注。然而,皮肤的主要屏障角质层极大地限制了大部分药物的药效。微针（MNs）可穿透角质层,为药物经皮渗透创造瞬时微通道,从而递送药物至真皮层或皮下。同时MNs给药微创、操作简单、无痛且药物可控释放,因此在皮肤局部或全身给药具有广阔的应用前景。综述MNs的制备、分类及其应用于皮肤肿瘤治疗的最新研究进展,探讨MNs在生物医药研究领域的发展前景,为MNs经皮给药系统应用于临床提供参考。     

Transdermal Controlled Administration of Indomethacin. I. Enhancement of Skin Permeability

It was observed experimentally that indomethacin delivered in an aqueous suspension has a greater skin permeation rate in an ionized form than in a nonionized form. In this investigation, a matrix-type transdermal drug delivery system was developed to deliver indomethacin molecules in nonionized form. The skin permeation rate of nonionized indomethacin molecules from this system could be substantially improved by incorporating skin permeation enhancers, such as straight-chained alkanols, alkanoic acids, and esters. These enhancers form microreservoirs with indomethacin in the lipophilic silicone polymer matrix. By varying the alkyl chain length of alkanol, alkanoic acid, and its ester, the concentration of permeation enhancer, or the loading dose of indomethacin in the polymer matrix, the skin permeation rate of nonionized indomethacin molecules can be enhanced by as much as 30 times, which is almost sevenfold greater than the rate for ionized indomethacin molecules.     

Investigating effect of microemulsion components: In vitro permeation of ketoconazole

The purpose of this study was to evaluate the effect of oil, surfactant/co-surfactant mixing ratios and water on the in vitro permeation of ketoconazole (KTZ) applied in O/W microemulsion vehicle through intact rat skin. Lauryl Alcohol (LA) was screened as the oil phase of microemulsions, due to a good solubilizing capacity of the microemulsion system. The pseudo-ternary phase diagrams for microemulsion regions were constructed using LA as the oil, Labrasol (Lab) as the surfactant (S) and ethanol (EtOH) as the cosurfactant (CoS). The formulation which showed a highest permeation rate of 54.65?±?1.72 µg/cm²/h¹ and appropriate physico-chemical properties was optimized as containing 2% KTZ, 10% LA, 20% Lab/EtOH (1:1) and 68% double distilled water (w/w). The efficiency of microemulsion formulation in the topical delivery of KTZ was dependent upon the contents of water and LA as well as Lab/EtOH mixing ratio. It was concluded that the percutaneous absorption of KTZ from microemulsions was enhanced with increasing the LA and water contents, and with decreasing the Lab/EtOH ratio in the formulation. Candida albicans was used as a model fungus to evaluate the antifungal activity of the best formula achieved, which showed the widest zone of inhibition as compared to KTZ reference. The studied microemulsion formulation showed a good stability for a period of three months. Histopathological investigation of rat skin revealed the safety of microemulsion formulations for topical use. These results indicate that the studied microemulsion formulation might be a promising vehicle for topical delivery of KTZ.     

Smart microneedle coatings for controlled delivery and biomedical analysis

Abstract

The work presented demonstrates an unconventional approach in the preparation of smart microneedle (MN) coatings utilising electrohydrodynamic atomisation (EHDA) principles. Stainless steel (600–900?µm in height) MNs were coupled to a ground electrode (in the EHDA coating set-up) with the deposition distance and collecting methodology varied for an ethanol:methanol (50:50) vehicle system. The preparation of nano- and micrometre-scaled pharmaceutical coatings was achieved. Fluorescein dye (serving as potential drug, sensory materials or disease state markers) and polyvinylpyrrolidone (PVP, polymer matrix system) formed the remaining components of the coating formulation. Based on these excipients and by varying the coating process, particles (100?nm to 3?µm) and fibres (400?nm to 1?µm) were deposited directly on MNs in controlled and selectable fashion (flow rates variable ～5–50?µL/min, applied voltage variable 6–19?kV). These demonstrated options for multiple targeting and analysis applications. The underlying EHDA process permits room temperature fabrication, controlled output and scale-up potential for emerging MN devices as drug systems or lab-chip testing devices.     

Development of Hydrogels for Microneedle-Assisted Transdermal Delivery of Naloxone for Opioid-Induced Pruritus

Transdermal naloxone delivery could be a potential option for treating opioid-induced pruritus, but naloxone does not permeate skin well because of its hydrophilic nature. Microneedles (MNs) could overcome the skin barrier by painlessly creating microchannels in the skin to permit naloxone absorption to therapeutic levels. This study investigated how ionization correlates with naloxone permeation across MN-treated skin. Hydrogels containing 0.2, 0.5, or 1% naloxone were formulated with 1% cross-linked polyacrylic acid (polymer) and adjusted to pH 5, 6.5, or 7.4. Porcine skin was treated with MNs and naloxone gel, and in vitro permeation studies were performed using an in-line diffusion setup. Gel structural properties were evaluated using rheology. All gels had viscoelastic properties and good spreadability. Naloxone permeation through intact skin was highest from pH 7.4 gels when naloxone is unionized, in contrast with undetectable concentrations permeated from pH 5 gels with 100% ionization. Combining MN treatment with pH 5 gels significantly enhanced permeation and resulted in steady-state flux that would achieve therapeutic delivery. Absorption lag time was affected by MN length and naloxone gel concentration. Polymer concentration did not influence drug permeability. This study demonstrates that transdermal naloxone delivery with MNs is a viable treatment option for opioid-induced pruritus.     

Effect of fatty acids on the transdermal delivery of donepezil: in vitro and in vivo evaluation

The effect of fatty acids on the skin permeation of donepezil base (DPB) and its hydrochloride salt (DPH) were studied in vitro using hairless mouse and human cadaver skin. DPB and DPH were solubilized in propylene glycol (PG) containing 1% (w/v) fatty acid, after which the in vitro permeation through hairless mouse skin and human cadaver skin were evaluated using Keshary-Chien diffusion cells. The optimized formulation obtained from the in vitro study was then tested in rats for an in vivo pharmacokinetic study. The relative in vitro skin permeation rate of donepezil (DP) through the hairless mouse skin showed a parabolic relationship with increased carbon length of the fatty acid enhancers. Among the fatty acids tested, oleic acid for DPB and palmitoleic acid for DPH showed the highest enhancing effect, respectively. Both the permeation rates of DPB and DPH evaluated in human cadaver skin were in good correlation with those in hairless mouse skin, regardless of the presence of fatty acids. This suggests that the mouse skin model serves as a useful in vitro system that satisfactorily represents the characteristics of the human skin. Moreover, based on the in vitro results, the optimal formulation that could maintain the human plasma concentration of 50 ng/mL was determined to be 10mg DP with 1% (w/v) enhancer. When the DP transdermal formulations were applied to the abdominal skin of rats (2.14 cm(2)), the C(ss) was maintained for 48 h, among which the highest value of 52.21 ± 2.09 ng/mL was achieved with the DPB formulation using oleic acid. These results showed that fatty acids could enhance the transdermal delivery of DP and suggested the feasibility of developing a novel transdermal delivery system for clinical use.