Novel sugar esters proniosomes for transdermal delivery of vinpocetine: Preclinical and clinical studies

Vinpocetine (Vin) existing oral formulations suffer poor bioavailability (∼7%) since Vin undergoes a marked first-pass effect (∼75%) and its absorption is dissolution rate-limited. In this study, a novel sustained release proniosomal system was designed using sugar esters (SEs) as non-ionic surfactants in which proniosomes were converted to niosomes upon skin water hydration following topical application under occlusive conditions. Different in vitro aspects (encapsulation efficiency, vesicle size and shape, effect of occlusion, in vitro release, skin permeation and stability) were studied leading to an optimized formula that was assessed clinically for transdermal pharmacokinetics and skin irritation.All formulae exhibited high entrapment efficiencies, regardless of the surfactant HLB. Vesicle size analysis showed that all vesicles were in the range from 0.63 μm to 2.52 μm which favored efficient transdermal delivery. The extent of drug permeation through the skin from the optimized formula - containing laurate SE with shorter fatty acid chain length and high HLB - was quite high (91%) after 48 h under occlusive conditions. The extent of absorption of Vin from proniosomes was larger when compared to the oral tablet with a relative bioavailability (F_rel) of 206%. Histopathological evaluation revealed only moderate skin irritation when using SEs compared to skin inflammation when using Tween 80. Sugar esters proniosomes may be a promising carrier for vinpocetine, especially due to their simple scaling up and their ability to control drug release.     

Oleodendrimers: A novel class of multicephalous heterolipids as chemical penetration enhancers for transdermal drug delivery

This paper reports synthesis and evaluation of Janus type generation G-1 and G-2 dendrimers. The dendrimers have been constructed by linking two building blocks, dendrons and oleic acid, through ester and amide bonds and were well characterized by Fourier-transform infrared (FT-IR), ¹H NMR, ¹³C NMR and electrospray ionization mass spectrometry (ESI-MS). The dendrimers have been evaluated for in vitro cytotoxicity using sulforhodamine B assay (SRB assay) and in vivo skin irritation potential. The ester linked dendrimers did not exhibit any cytotoxicity even up to 80 μg/ml while G-1 and G-2 generations dendrimers with amide linkage exhibited toxicity above 70 μg/ml and 21 μg/ml, respectively, none of the dendrimers showed any skin irritation. All the dendrimers, tested for their skin permeation enhancement potential using diclofenac sodium (DS) as a model drug at a concentration of 1% in gels, showed significant increase in steady-state flux (ER_flux) of the drug as compared to control (without enhancer), and oleic acid. Amongst the dendrimers, the ester linked G-1 and G-2 dendrimers showed highest ER_flux, 3.33 ± 0.31 and 3.39 ± 0.21, respectively.     

Effect of iontophoresis on in vitro transdermal absorption of almotriptan

The aim of the present work was to characterize the in vitro transdermal absorption of almotriptan through pig ear skin. The passive diffusion of almotriptan malate and its iontophoretic transport were investigated using current densities of 0.25 and 0.50 mA/cm². In vitro iontophoresis experiments were conducted on diffusion cells with an agar bridge without background electrolytes in the donor compartment. Although both current densities applied produced a statistically significant increment with respect to passive permeation of almotriptan (p < 0.01), that of 0.50 mA/cm² proved to be the best experimental condition for increasing the transport of almotriptan across the skin. Under these experimental conditions, the transdermal flux of the drug increased 411-fold with respect to passive diffusion, reaching 264 ± 24 μg/cm² h (mean ± SD). Based on these results, and taking into account the pharmacokinetics of almotriptan, therapeutic drug plasma levels for the management of migraine could be achieved via transdermal iontophoresis using a reasonably sized (around 7.2 cm²) patch.     

Low frequency sonophoresis mediated transdermal and intradermal delivery of ketoprofen

The objective of this study was to test low frequency sonophoresis at 20 kHz for delivery of ketoprofen into and across the skin. Permeation studies were carried out in vitro on excised hairless rat skin over a period of 24 h using Franz diffusion cells after which, skin samples were subjected to skin extraction to quantify the amount of drug present in skin. Parameters like ultrasound application time, duty cycle coupling medium and distance of ultrasound horn from skin were optimized. Transepidermal water loss (TEWL) was measured to indicate the extent of barrier disruption following sonophoresis. Confocal microscopy was used to visualize dye penetration through sonophoresis treated skin. Application of ultrasound significantly enhanced permeation of ketoprofen from 74.87 ± 5.27 μg/cm² for passive delivery to 491.37 ± 48.78 μg/cm² for sonophoresis. Drug levels in skin layers increased from 34.69 ± 7.25 μg following passive permeation to 212.62 ± 45.69 μg following sonophoresis. TEWL increased from 31.6 ± 0.02 (passive) to 69.5 ± 12.60 (sonophoresis) indicating disruption of barrier properties. Confocal microscopy images depicted enhanced dye penetration through sonophoresis treated skin confirming barrier disruption. Low frequency sonophoresis with optimized ultrasound parameters can be effectively used to actively enhance transdermal and topical delivery of ketoprofen.     

In vivo and in vitro skin absorption of lipophilic compounds,dibutyl phthalate,farnesol and geraniol in the hairless guinea pig

The relationship between in vitro and in vivo skin absorption of lipophilic cosmetic ingredients (dibutyl phthalate (DBP, Log K_ow: 4.45), farnesol (Log K_ow: 5.77) and geraniol (Log K_ow: 3.56) from an oil-in-water emulsion was investigated in the hairless guinea pig. In vivo absorption of DBP, farnesol and geraniol 24 h after dermal application was 62.0 ± 2.0, 39.8 ± 2.5, and 15.1 ± 1.8% of the applied dose (%AD), respectively. In vitro absorption was measured at 24 and 72 h by using flow-through diffusion cells (0.64 cm²) with a receptor fluid consisting of HHBSS + 4% BSA. In vitro studies of DBP, farnesol and geraniol absorption over 24 h found 27.1 ± 1.9, 43.5 ± 3.3 and 45.9 ± 3.2%AD in receptor fluid, respectively, and over 72 h found 59.9 ± 3.2, 77.5 ± 7.1 and 49.0 ± 6.3%AD, respectively. We found that the amount of DBP absorbed in vivo after 24 h closely agreed with the amount of DBP found in the receptor fluid in vitro after 72 h. In contrast, the amount of topically applied farnesol absorbed in vivo after 24 h was similar to the amount of farnesol found in receptor fluid in vitro after 24 h. A direct comparison between the in vivo absorption of geraniol and the in vitro absorption at 24 and 72 h was not meaningful due to the rapid evaporation of geraniol from the skin. Our in vitro results suggest that lipophilic chemicals initially form a reservoir in skin, and the material in the reservoir may ultimately diffuse out of the skin into the receptor fluid within 72 h. Our results also demonstrate the utility of in vivo studies for resolving questions about the fate of lipophilic chemicals remaining in skin after in vitro absorption studies.     

Improved photostability and reduced skin permeation of tretinoin: Development of a semisolid nanomedicine

The aims of this work were to increase the photostability and to reduce the skin permeation of tretinoin through nanoencapsulation. Tretinoin is widely used in the topical treatment of various dermatological diseases such as acne, psoriasis, skin cancer, and photoaging. Tretinoin-loaded lipid-core polymeric nanocapsules were prepared by interfacial deposition of a preformed polymer. Carbopol hydrogels containing nanoencapsulated tretinoin presented a pH value of 6.08 ± 0.14, a drug content of 0.52 ± 0.01 mg g⁻¹, pseudoplastic rheological behavior, and higher spreadability than a marketed formulation. Hydrogels containing nanoencapsulated tretinoin demonstrated a lower photodegradation (24.17 ± 3.49%) than the formulation containing the non-encapsulated drug (68.64 ± 2.92%) after 8 h of ultraviolet A irradiation. The half-life of the former was seven times higher than the latter. There was a decrease in the skin permeability coefficient of the drug by nanoencapsulation, independently of the dosage form. The liquid suspension and the semisolid form provided K_p = 0.31 ± 0.15 and K_p = 0.33 ± 0.01 cm s⁻¹, respectively (p ? 0.05), while the samples containing non-encapsulated tretinoin showed K_p = 1.80 ± 0.27 and K_p = 0.73 ± 0.12 cm s⁻¹ for tretinoin solution and hydrogel, respectively. Lag time was increased two times by nanoencapsulation, meaning that the drug is retained for a longer time on the skin surface.     

A dynamic topical hydrofluoroalkane foam to induce nanoparticle modification and drug release in situ

Topical nanoparticles are usually applied using semi-solid formulations, but the delivery process is often inefficient due to the poor drug release from the particles. The aim of this study was to investigate the capability of a dynamic foam to break open nanoparticles upon application to the skin and enhance drug delivery efficiency. Vitamin E acetate (VEAc) was selected as a model drug and loaded into lipid nanoparticles (50-60 nm) prepared by phase inversion. The highest drug loading was 18.9 ± 1.2 mg/ml and the corresponding encapsulation efficiency was 81.5 ± 4.1%. Dynamic foams were generated by emulsifying VEAc-loaded nanoparticle suspensions with hydrofluoroalkane using pluronic L62D. An in vitro permeation study demonstrated that VEAc did not release from the nanoparticles when administered as an aqueous suspension, but attained a flux of 18.0 ± 2.1 (μg cm⁻² h⁻¹) when applied using the foam. Drug release from the foam was shown to be a consequence of nanoparticle modification after dose administration and this led to the foam delivering 0.7 ± 0.3% VEAc into the stratum corneum (SC) when applied to human skin.     

Skin Irritation in Transdermal Drug Delivery Systems: A Strategy for its Reduction

Purpose Active pharmaceutical ingredients (API) in transdermal drug delivery systems (TDS) often causes skin irritation such as erythema and edema. We have studied a possible approach for the reduction of skin irritation by patch formulations that control the rates of skin permeation and elimination of API. Methods Loxoprofen (LX-base) was used to induce the skin irritation. The redness value (Δa) was evaluated as a measure of erythema by Chroma Meter. The in vitro skin permeation and release profiles were also investigated by using a side-by-side diffusion cell. Results The redness values were not correlated either with the cumulative amount of API permeated or the concentration of LX-base in the skin, but well correlated with the elimination rate of LX-base from the skin after the removal of the formulation. The formulation with gradual decrease of permeation rate during application accelerated the elimination rate after application, and resulted in the reduction of the skin irritation. Conclusions The skin pharmacokinetics of API, not only permeation during application but also release after the patch removal, was found to be a significant factor for skin irritation. To minimize the skin irritation, it’s also important to eliminate the residual API in the skin promptly after application.     

Development of sucrose stearate-based nanoemulsions and optimisation through γ-cyclodextrin

Nanoemulsions aimed at dermal drug delivery are usually stabilised by natural lecithins. However, lecithin has a high tendency towards self-aggregation and is prone to chemical degradation. Therefore, the aim of this study was to develop nanoemulsions with improved structure and long-term stability by employing a natural sucrose ester mixture as sole surfactant. A thorough comparison between the novel sucrose stearate-based nanoemulsions and corresponding lecithin-based nanoemulsions revealed that the sucrose ester is superior in terms of emulsifying efficiency, droplet formation as well as physical and chemical stability. The novel formulations exhibited a remarkably homogeneous structure in cryo TEM investigations, as opposed to the variable structure observed for lecithin-based systems. The in vitro skin permeation rates of lipophilic drugs from sucrose stearate nanoemulsions were comparable to those obtained with their lecithin-based counterparts. Furthermore, it was observed that addition of γ-cyclodextrin led to enhanced skin permeation of the steroidal drug fludrocortisone acetate from 9.99 ± 0.46 to 55.10 ± 3.67 μg cm⁻² after 24 h in the case of sucrose stearate-based systems and from 9.98 ± 0.64 to 98.62 ± 24.89 μg cm⁻² after 24 h in the case of lecithin-based systems. This enhancement effect was significantly stronger in formulations based on lecithin (P < 0.05), which indicates that synergistic mechanisms between the surfactant and the cyclodextrin are involved. Cryo TEM images suggest that the cyclodextrin is incorporated into the interfacial film, which might alter drug release rates and improve the droplet microstructure.     

Using laser microporation to improve transdermal delivery of diclofenac: Increasing bioavailability and the range of therapeutic applications

The objective of the study was to investigate the effect of laser microporation, using P.L.E.A.S.E.® technology, on diclofenac delivery kinetics. Skin transport of diclofenac was studied from aqueous solution, propylene glycol and marketed formulations across intact and laser-porated porcine and human skins; cumulative permeation and skin deposition were quantified by HPLC. After 24 h, cumulative diclofenac permeation across skins with 150, 300, 450 and 900 shallow pores (50-80 μm) was 3.7-, 7.5-, 9.2- and 13-fold superior to that across untreated skin. It was also found to be linearly dependent on laser fluence; Permeation (μg/cm²) = 11.35 * Fluence (J/cm²) + 352.3; r² = 0.99. After 24 h, permeation was 539.6 ± 78.1, 934.5 ± 451.5, 1451.9 ± 151.3 and 1858.6 ± 308.5 μg/cm², at 22.65, 45.3, 90.6 and 135.9 J/cm², respectively. However, there was no statistically significant effect of laser fluence on skin deposition. Diclofenac delivery from marketed gel formulations was also significantly higher across laser-porated skins (e.g. for Solaraze™, cumulative permeation after 24 h across treated (900 pores/135.9 J/cm²) and untreated skin was 974.9 ± 368.8 and 8.2 ± 3.8 μg/cm², respectively. Diclofenac delivery from Solaraze™ across laser-porated porcine and human skins was also shown to be statistically equivalent. The results demonstrated that laser microporation significantly increased diclofenac transport from both simple and semi-solid formulations through porcine and human skin and that pore depth and pore number could modulate delivery kinetics. A similar improvement in topical diclofenac delivery in vivo may increase the number of potential therapeutic applications.     

川丁特罗贴剂的设计及分子机制研究

目的 采用离子对与促透剂联合应用的促透策略，设计一种经皮透过性良好的川丁特罗贴剂，用于支气管哮喘的治疗。方法 首先采用有机溶媒挥散法制备川丁特罗经皮吸收贴剂，以Wistar大鼠皮肤为模型，采用单因素考察法在体外经皮透过试验中考察离子对与促透剂的联用对川丁特罗经皮透过行为的影响并优选贴剂处方。通过贴剂体外释放试验和红外光谱试验，探讨离子对及促透剂对川丁特罗经皮透过行为的影响及分子机制。结果 贴剂的优选处方为川丁特罗-对氨基苯甲酸为主药，载药量为5%，DURO-TAK^®87-4098为压敏胶基质，8%聚甘油油酸酯为促透剂。离子对的形成增加了川丁特罗的皮肤渗透性，而聚甘油油酸酯的加入对川丁特罗从贴剂中的释放和川丁特罗皮肤透过均有促进作用，2个技术的联用增加了川丁特罗的皮肤累积透过量。结论 本研究通过采用离子对与促透剂联合应用的策略，成功设计了川丁特罗压敏胶分散型贴剂，并从释放和经皮吸收2方面探讨了离子对和促透剂的作用机制，为开发川丁特罗贴剂提供参考。     

Preparation,characterization and pharmacological evaluation of tolterodine hydrogels for the treatment of overactive bladder

In this study, transdermal gel formulations for tolterodine were developed to investigate the effects of gel matrix and chemical enhancers on drug skin permeation from tolterodine hydrogels. In vitro permeation studies of tolterodine through excised mouse skin were carried out using Franz-type diffusion cells. In the optimum gel formulation, Carbopol 940 was selected as the gel matrix. Compared to gels without enhancer, tolterodine hydrogels with N-methyl pyrrolidone (NMP) showed significant enhancing effect on transdermal permeation of tolterodine (p < 0.05). The results of in vitro percutaneous delivery experiment showed that the relationship of the steady accumulative percutaneous amount (Q, μg cm⁻²) of tolterodine hydrogels and time was Q_4–12h = 770.19t^1/2 − 966.99. Tolterodine permeated at the steady-state speed of 770.19 μg cm⁻² h⁻¹ and its release coincided with Higuchi Equation. The pharmacokinetic properties of the optimized tolterodine formulation were studied in rabbits. The absolute bioavailability of tolterodine was 11.47%. Since the absence of hepatic first-pass metabolism, only a single active compound-tolterodine was detected in the plasma. A skin irritation study was also carried out on rabbits, and the results showed tolterodine hydrogels had no skin irritation. In the pharmacodynamic study, the significant effects of tolterodine hydrogels on the inhibition of pilocarpine-induced rat urinary bladder contraction were last to 12 h, indicating that tolterodine hydrogels could produce prolonged pharmacological responses. In conclusion, tolterodine hydrogels were formulated successfully using Carbopol 940 and NMP and these results helped in finding the optimum formulation for percutaneous drug release. It is quite evident that tolterodine hydrogels may offer a possibility to avoid the first-pass effect, resulting in a single active compound of tolterodine in plasma, which may profit on the patient under the dose control and the reduction of potential adverse effect from two active compounds in the body.     

Microdialysis assessment of percutaneous penetration of ketoprofen after transdermal administration to hairless rats and domestic pigs

The study was performed to evaluate the percutaneous penetration of ketoprofen after transdermal administration using a microdialysis technique in pigs, in comparison with rats. Ketoprofen release from patches was determined by analysis of the remaining drug content after application to hairless rats and pigs. Skin and knee joint penetration of ketoprofen was tested by microdialysis, and recovery was determined by retrodialysis. Residual rates in hairless rats and pigs were 68.1 ± 1.6% and 81.7 ± 4.4%, respectively, at 10 h. The average recoveries of ketoprofen over 480 min in the skin and knee joint cases were 72.0 ± 3.4% and 9.8 ± 6.2% in rats and 72.3 ± 2.5% and 57.6 ± 3.1% in pigs, respectively. In rats, ketoprofen was rapidly absorbed with transdermal administration, with C_max values of 191.7 ± 76.2 and 35.5 ± 21.7 ng/mL and AUC_0-8h values of 918.2 ± 577.5 and 195.9 ± 137.1 ng h/mL, respectively, for the skin and knee joint. The C_max values for the pig were 20.9 ± 18.5 and 3.7 ± 3.0 ng/mL, with AUC_0-8h values of 73.1 ± 69.2 and 16.1 ± 16.1 ng h/mL. Ketoprofen concentrations within skin and knee joint of non-application sites in rats and pigs were less than 0.8 ng/mL. Transdermal administration of ketoprofen significantly reduced prostaglandin E2 levels in the skin of the application site and showed a tendency for inhibition in the knee joint. We thus demonstrated that topical patches containing ketoprofen can deliver the drug through the skin and knee joint of pigs and rats via direct diffusion, and microdialysis data with the pig may be useful for the prediction of human tissue penetration of drugs with transdermal administration.     

Carboxymethylcellulose-sodium Based Transdermal Drug Delivery System for Propranolol

Propranolol, a β-adrenoceptor blocker, suffers from a high degree of first-pass metabolism resulting in very low bioavailability (<10%) following administration with conventional oral formulations. To circumvent this significant therapeutic hurdle, we formulated a carboxymethylcellulose-sodium (CMC-Na) based transdermal system for propranolol and evaluated the patch for its in-vitro and in-vivo performance. In-vitro permeation studies using the excised hair-free rat skin model resulted in 66.54% permeation at the end of 24 h in a modified Franz diffusion cell. This zero-order permeation profile was characterized by a drug permeation rate of 52.87 ± 11.63 μg cm^?2 h^?1. Skin irritation studies in rats (n = 5), evaluated for flare-and-wheal with respect to a formalin control, indicated that the drug-containing patch evoked only a mild response over a 7-day period. Preliminary in-vivo studies in male albino rabbits (n = 3), indicated that plasma drug levels averaged 11.75 ± 3.40 ng mL^?1 in a 24-h study period before patch removal.     

Enhancing effect of switching iontophoresis on transdermal absorption of glibenclamide

Glibenclamide(GLI) is widely used as an oral hypoglycemic drug in the treatment of non-insulin dependent diabetes mellitus (NIDDM). We investigated The enhancing effect of switching iontophoresis on the transdermal absorption and reduction of skin irritation to develop a transdermal dosage form of GLI. The 0.1% of Gli suspensions in 0.2 M tris-HCl buffer of pH 7.4, 8.0 and 8.5 were prepared as donor solutions. We examined drug permeation through the excised rat abdominal skin, drug absorption in rats and reduction of skin irritation after application of switching iontophoresis for 1 h using DC 10 V. The solubility of GLI in 0.2 M tris-HCl buffer increased with a rise in pH. In the permeation study, GLI was permeated continuously and the cumulative amount of permeated GLI increased using an alkaline donor solution. In the drug absorption study, the application group of pH 8.5 gave higher plasma concentration levels than those of pH 7.4 and 8.0 groups. The skin irritation evoked by the application of iontophoresis was pathologically studied. A total irritation score (TIS) was estimated as a judging standard for the skin damage. The TIS value increased dependently with a rise in pH. However, it was considered that the skin irritations were not serious and small matters. The results demonstrate the possibility of iontophoretic transdermal administration of GLI and the effect of drug solubility in the donor solution on the absorption of GLI.     

Evaluation of skin permeation and anti-inflammatory and analgesic effects of new naproxen microemulsion formulations

The aim of this study was to evaluate the potential application of microemulsions as a transdermal drug delivery for naproxen (Np). The pseudo-ternary phase diagrams were developed for microemulsions composed of isopropyl myristate, Span 80, Labrafil M, Labrasol, and Cremophor EL, ethanol and isopropyl alcohol and 0.5 N sodium hydroxide. The final concentration of Np in microemulsion systems was 10% (w/w). The microemulsions were characterised by conductivity, droplet size, viscosity and pH. Moreover, in vitro permeability studies were performed using diffusion cells from rat skin. The permeation rates of Np from microemulsions (M1_Np and M2_Np) were higher than the commercial (C) gel formulation. The paw oedema test was performed in rats to evaluate the anti-inflammatory activity of Np. The volume increase in paw oedema after 6 hr was 0.71 ± 0.46% with M2_Np, whereas M1_Np and C exhibited 6.48 ± 2.71% and 14.97 ± 3.15% increases in oedema, respectively. Additionally, a significant analgesic effect was detected in the hot plate and tail-flick tests for all test microemulsion and C formulations when compared with the control. Histopathological examination of the treated skin was performed to investigate changes in skin morphology. In conclusion, the microemulsion formulations, especially the M2_Np formulation, may be used as an effective alternative for the transdermal delivery of Np.     

Use of the skin sandwich technique to probe the role of the hair follicles in sonophoresis

The human skin sandwich technique was used to explore the effect of brief ultrasound exposure on the transfollicular pathway of absorption. Hydrocortisone was used as a model drug. In order to calculate the permeability coefficient of hydrocortisone, its concentration at saturation in the PBS donor solution was determined. Skin samples were prepared by sandwich technique with total hydration of the epidermal and sandwich membranes. The skin was sonicated for 0 s (control), 30 s or 45 s using a pulsed mode (10% duty cycle) with the spatial and temporal average intensity (SATA) of 3.7 W/cm². The transducer was then removed and permeation was allowed to proceed for 52 h. Then the percentage follicular contribution was determined. It was determined that without ultrasound, drug entry into follicles accounted for 46% of total penetration. As the duration of sonication increased, the follicular contribution fell to zero even though total transepidermal flux dramatically increased. This is explained by ultrasound exposure causing sloughing off of the uppermost stratum corneum. This permeabilises the continuous surface but at the same time the disturbed cornceocytes will plug hair follicle orifices.     

In vitro and in vivo iontophoretic transdermal delivery of an anti-parkinsonian agent

To objective of this work was to study the feasibility of iontophoretic delivery of SLV 318 (7-(4-benzyl-1-piperazinyl)-2(3H)-benzoxazolone methanesulfonate) across hairless rat skin in vitro and in vivo. The effect of counter-ions and temperature were investigated for optimizing SLV 318 solubility. The effect of electrode efficiency and total current applied on the delivery of SLV 318 were studied using Franz diffusion cells and samples were analyzed using HPLC. Delivery increased with increasing concentration. For current-time combinations, electrode had to be replaced every 9 h. Passive, iontophoretic (0.1 mA/cm² for 1 h) and intravenous studies were performed in vivo. Blood samples collected were analyzed using LC-MS/MS. SLV 318 had higher solubility with NaCl (75 mM) as a counter-ion at 25 °C than with other counter-ions tested. In vivo iontophoresis significantly enhanced the permeation and also reduced its lag time (P < 0.05). The C_max of SLV 318 during 1 h iontophoresis was 6.56 ± 0.68 ng/mL at 1.31 ± 0.29 h (T_max) as compared to 2.96 ± 0.29 ng/mL at 25.32 ± 0.67 h (T_max) by 24 h passive permeation. The in vitro and in vivo data has shown the feasibility to enhance delivery of SLV 318 by iontophoresis.     

Skin permeation enhancement effect and skin irritation of saturated fatty alcohols

Though the skin permeation enhancement effect of chemical penetration enhancers has been studied extensively, their skin irritation potential has not been adequately investigated. The objective of this study was to evaluate the skin permeation enhancement effect and skin irritation of saturated fatty alcohols using melatonin as a model compound. A saturated solution of melatonin in a mixture of water and ethanol (40:60) containing 5% w/v of saturated fatty alcohol was used in the skin permeation studies using Franz diffusion cells. For skin irritation studies, 230 microl of fatty alcohol solution was applied on the dorsal surface of the hairless rats using Hill top chamber. The skin irritation was evaluated by visual scoring method and bioengineering methods such as measurement of transepidermal water loss (TEWL) and skin blood flow. The flux of melatonin across hairless rat skin was found to be dependent on the carbon chain length of the fatty alcohols, with decanol showing the maximum permeation of melatonin. All fatty alcohols increased the TEWL and skin blood flow significantly compared with the vehicle. The fatty alcohols (decanol, undecanol and lauryl alcohol), which showed greater permeation of melatonin, also produced greater TEWL, skin blood flow and erythema. Tridecanol and myristyl alcohol showed lower permeation enhancement effect but caused greater skin irritation. Octanol and nonanol may be the most useful enhancers for the transdermal delivery of melatonin considering their lower skin irritation and a reasonably good permeation enhancement effect. However, further studies are needed to ascertain their safety as skin penetration enhancers. Skin permeation and skin irritation in experimental animals such as rats are generally higher compared with human skin. Further studies in human volunteers using fatty alcohols at the concentrations of 5% or lower may provide useful information on the utility of these fatty alcohols as permeation enhancers.     

Natural oils as skin permeation enhancers for transdermal delivery of olanzapine: in vitro and in vivo evaluation

The feasibility of development of transdermal delivery system of olanzapine utilizing natural oils as permeation enhancers was investigated. Penetration enhancing potential of corn (maize) oil, groundnut oil and jojoba oil on in vitro permeation of olanzapine across rat skin was studied. The magnitude of flux enhancement factor with corn oil, groundnut oil and jojoba oil was 7.06, 5.31 and 1.9 respectively at 5mg/ml concentration in solvent system. On the basis of in vitro permeation studies, eudragit based matrix type transdermal patches of olanzapine were fabricated using optimized concentrations of natural oils as permeation enhancers. All transdermal patches were found to be uniform with respect to physical characteristics. The interaction studies carried out by comparing the results of ultraviolet, HPLC and FTIR analyses for the pure drug, polymers and mixture of drug and polymers indicated no chemical interaction between the drug and excipients. Corn oil containing unsaturated fatty acids was found to be promising natural permeation enhancer for transdermal delivery of olanzapine with greatest cumulative amount of drug permeated (1010.68 μg/cm2/h) up to 24 h and caused no skin irritation. The fabricated transdermal patches were found to be stable. The pharmacokinetic characteristics of the final optimized matrix patch (T2) were determined after transdermal application to rabbits. The calculated relative bioavailability of TDDS was 113.6 % as compared to oral administration of olanzapine. The therapeutic effectiveness of optimized transdermal system was confirmed by tranquillizing activity in rotarod and grip mice model.