Penetration Enhancers For Transdermal Delivery Research Articles

Fabrication of Tizanidine Loaded Patches Using Flaxseed Oil and Coriander Oil as a Penetration Enhancer for Transdermal Delivery.

Transdermal drug delivery is important to maintain plasma drug concentrations for therapeutic efficacy. The current study reports the design, formulation, and evaluation of tizanidine transdermal patches formulated using chitosan and thiolated chitosan, ethyl cellulose (EC), polyvinylpyrrolidone (PVP), and Eudragit RL100 in different ratios. The tizanidine patches were formulated using flaxseed oil and coriander oil in the concentrations of 1% v/w, 2% v/w, 3% v/w, 4% v/w, 5% v/w, and 10% v/w. The patches were subjected to characterization of physicochemical property (thickness, weight uniformity, drug content, efficiency, percentage moisture uptake/loss), in vitro drug release and drug permeation, skin irritation, in vivo application, pharmacokinetics analysis, and stability studies. The results indicate that the interaction of thiolated chitosan with the negative charges of the skin opens the tight junctions of the skin, whereas flaxseed and coriander oils change the conformational domain of the skin. The novelty of this study is in the use of flaxseed and coriander oils as skin permeation enhancers for the formulation of tizanidine transdermal patches. The formulations follow non-Fickian drug release kinetics. The FTZNE23, FTZNE36 and FTZNE54, with 5% v/w flaxseed oil loaded formulations, exhibited higher flux through rabbit skin compared with FTZNE30, FTZNE35, FTZNE42, and FTZNE47, formulations loaded with 10% v/w coriander oil. The study concludes that flaxseed oil is a better choice for formulating tizanidine patches, offering optimal plasma concentration and therapeutic efficacy, and recommends the use of flaxseed and coriander oil based patches as a novel transdermal delivery system for tizanidine and related classes of drugs.

EFFECT OF MENTHOL ON THE TRANSDERMAL PERMEATION OF ACECLOFENAC FROM MICROEMULSION FORMULATION

Objective: The aim of this investigation was to enhance the transdermal permeation of aceclofenac (ACF) from microemulsion formulation using menthol as a natural permeation enhancer.
 Methods: Microemulsion containing 2% w/v of ACF was prepared by a titration method with different concentration of oil, surfactant and co-surfactant. The prepared microemulsion was evaluated for droplet size, viscosity, pH and in vitro skin permeation studies. Menthol at 3-8% w/w was added to the selected microemulsion formulation and their effect on skin permeation was evaluated across rat epidermis using modified Keshary-Chien diffusion cell. The Fourier transform infrared spectroscopy (FT-IR) was performed to understand the regulation action of menthol in the skin permeability barrier.
 Results: The average droplet size of the microemulsion was found to be 89.4±2.12 to 175.2±3.10 nm. The transdermal flux of the microemulsion containing 8% w/w menthol showed 2.9 fold increases in transdermal flux of ACF compared with the formulation without menthol. Result of FT-IR studies showed decrease in peak height of the symmetric and asymmetric C-H stretching vibrations may be because of the extraction of the stratum corneum (SC) lipids and the alteration of the skin permeability barrier.
 Conclusion: This result suggests that menthol significantly enhanced the transdermal permeation of ACF and may be an effective natural penetration enhancer for transdermal delivery of the drug.

Transdermal permeation of drugs with differing lipophilicity: Effect of penetration enhancer camphor

The aim of the present study was to investigate the potential application of (+)-camphor as a penetration enhancer for the transdermal delivery of drugs with differing lipophilicity. The skin irritation of camphor was evaluated by in vitro cytotoxicity assays and in vivo transdermal water loss (TEWL) measurements. A series of model drugs with a wide span of lipophilicity (logP value ranging from 3.80 to −0.95), namely indometacin, lidocaine, aspirin, antipyrine, tegafur and 5-fluorouracil, were tested using in vitro transdermal permeation experiments to assess the penetration-enhancing profile of camphor. Meanwhile, the in vivo skin microdialysis was carried out to further investigate the enhancing effect of camphor on the lipophilic and hydrophilic model drugs (i.e. lidocaine and tegafur). SC (stratum corneum)/vehicle partition coefficient and Fourier transform infrared spectroscopy (FTIR) were performed to probe the regulation action of camphor in the skin permeability barrier. It was found that camphor produced a relatively low skin irritation, compared with the frequently-used and standard penetration enhancer laurocapram. In vitro skin permeation studies showed that camphor could significantly facilitate the transdermal absorption of model drugs with differing lipophilicity, and the penetration-enhancing activities were in a parabola curve going downwards with the drug logP values, which displayed the optimal penetration-enhancing efficiency for the weak lipophilic or hydrophilic drugs (an estimated logP value of 0). In vivo skin microdialysis showed that camphor had a similar penetration behavior on transdermal absorption of model drugs. Meanwhile, the partition of lipophilic drugs into SC was increased after treatment with camphor, and camphor also produced a shift of CH2 vibration of SC lipid to higher wavenumbers and decreased the peak area of the CH2 vibration, probably resulting in the alteration of the skin permeability barrier. This suggests that camphor might be a safe and effective penetration enhancer for transdermal drug delivery.

Quantification of nerolidol in mouse plasma using gas chromatography–mass spectrometry

Nerolidol is a naturally occurring sesquiterpene found in the essential oils of many types of flowers and plants. It is frequently used in cosmetics, as a food flavoring agent, and in cleaning products. In addition, nerolidol is used as a skin penetration enhancer for transdermal delivery of therapeutic drugs. However, nerolidol is hemolytic at low concentrations. A simple and fast GC–MS method was developed for preliminary quantification and assessment of biological interferences of nerolidol in mouse plasma after oral dosing. Calibration curves were linear in the concentration range of 0.010–5μg/mL nerolidol in mouse plasma with correlation coefficients (r) greater than 0.99. Limits of detection and quantification were 0.0017 and 0.0035μg/mL, respectively. The optimized method was successfully applied to the quantification of nerolidol in mouse plasma.

Novel Application of Natural Anisole Compounds as Enhancers for Transdermal Delivery of Ligustrazine.

To improve the transdermal delivery of ligustrazine, Foeniculum vulgare food origin anisole compounds were employed as promoters. Transdermal fluxes of ligustrazine were determined by Franz-type diffusion cells. Fourier transform-infrared (FT-IR) spectra were used to detect the biophysical changes of the stratum corneum and to explore the mechanism of permeation enhancement. A scanning electron microscope (SEM) was used to monitor the morphological changes of the skin. Among the three anisoles, anisic acid increased the penetration flux of ligustrazine significantly. The ligustrazine flux with anisic acid (11.9 μg/cm(2)/h) was higher than that any other group (p < 0.05). Spectra observations revealed that these anisole enhancers were able to disturb and extract the stratum corneum lipids. In addition, apparent density was used to describe the desquamation extent of the scutella. Multiple mechanisms are involved in the permeation enhancement of ligustrazine, including disturbing and extracting stratum corneum lipid, forming a competitive hydrogen bond. All data suggested that anisole compounds could be a group of safe and active penetration enhancers for transdermal delivery of ligustrazine.

Role of complexes formation between drugs and penetration enhancers in transdermal delivery

The use of chemical penetration enhancers (CPE) is growing due to their ability to improve drug delivery through the skin. A possible mechanism of penetration enhancement could involve the complex formation between drug and components in the pharmaceutical formulation, thus altering the physicochemical properties of the active substance. Here, modelling studies indicate that hydrocarbon and oxygen-containing terpenes (penetration enhancers) could form complexes with drugs. Satisfactory correlations have been obtained between the predicted molecular properties of enhancers and their enhancement effects.

Basil Oil is a Promising Skin Penetration Enhancer for Transdermal Delivery of Labetolol Hydrochloride

Thepresent work investigates effectiveness of basil oil, a volatile oil containing alcoholic terpenes, as a potential penetration enhancer for improved skin permeation of labetolol hydrochloride (LHCl) with reference to camphor, geraniol, thymol, and clove oil. Saturation solubilities of LHCl were determined in water, vehicle (ethanol:water, 60:40 v/v) and vehicle containing 5% w/v terpenes. Comparable (P > 0.05) saturation solubilities were found suggesting an insignificant increase in LHCl flux across rat skin on account of thermodynamic activity. Permeation of LHCl in vehicle per se and in presence of 5% w/v enhancer was investigated by performing in vitro rat abdominal skin permeation studies using a side-by-side glass diffusion cell. Various parameters viz. steady state flux, permeability coefficient, lag time, partition coefficient, diffusion coefficient, and enhancement ratios (ER) were calculated from the permeation data. Basil oil produced the maximum enhancement (ER = 46.52) over neat vehicle, among all enhancers. Activation energies for LHCl permeation in water, vehicle per se and in presence of 5% w/v basil oil were found to be 23.16, 18.71, and 10.98 kcal/mole, respectively. Lowering of activation energy in presence of basil oil suggests creation of new polar pathways in the skin for enhanced permeation of LHCl. Basil oil is proposed as a promising penetration enhancer for improved transdermal drug delivery of labetolol.

Transdermal iontophoretic delivery of bovine insulin and monomeric human insulin analogue

The present study was undertaken to explore the possibility of delivering bovine insulin in streptozocin (STZ)-induced diabetic rats by iontophoresis. Further, the effect of iontophoresis of monomeric human insulin analogue (r-DNA origin) on the plasma glucose level (PGL) of diabetic rats was studied. Iontophoresis of bovine insulin (10–200 IU/ml) was not effective in decreasing the PGL in untreated diabetic rats. Pretreatment of skin with oleic acid or menthol for 3 h followed by iontophoresis of bovine insulin also failed to produce a fall in PGL. Application of a depilatory cream for hair removal (24 h before the experiment), followed by iontophoresis of bovine insulin (10, 30 and 100 IU/ml) produced a concentration-dependent fall in PGL. Further, application of depilatory cream immediately before the experiment produced a substantial fall in PGL both by passive diffusion and iontophoresis. Depilatory cream might have drastically reduced the barrier function of skin such that conventional bovine insulin (dimer and hexamer) penetrates through the intact skin by iontophoresis and even by passive diffusion. Depilatory cream or the active components of depilatory cream may be useful as penetration enhancers for transdermal delivery of drugs especially macromolecules such as insulin. Iontophoresis of monomeric human insulin analogue (B9 Asp, B27 Glu) through intact skin (untreated) produced a significant fall in PGL in diabetic rats. Monomeric human insulin analogues which have low tendency to self aggregation may be promising candidates for the transdermal iontophoretic delivery of insulin.