Influence Of Penetration Enhancers Research Articles

Preparation and characterization of diclofenac transdermal patch using ethyl cellulose and polyvinyl alcohol by electrospinning

In recent years, the adverse effects linked to the oral administration of diclofenac, a non-steroidal anti-inflammatory drug (NSAID), have urged interest in exploring alternative administration routes, specifically transdermal drug delivery (TDD). Among the techniques emerging for creating nanoscale fibres suitable for TDD systems, electrospinning has attracted attention. The primary objective of this study was to formulate and evaluate nanofibers loaded with diclofenac diethylamine using ethylcellulose (EC) and polyvinyl alcohol (PVA) polymers. The influence of penetration enhancers, namely farnesol and nerolidol, on the properties of these fibres was investigated. Employing the electrospinning technique, nanofibers composed of EC or PVA polymers, with or without penetration enhancers, were fabricated, all maintaining a constant drug-to-polymer ratio. Mechanical strength and release kinetics from a cellophane membrane for the obtained nanofibers were investigated. A Franz diffusion cell was employed to determine the drug penetration rates through rat skin for selected fibre formulations. To gain insights into potential interactions and changes in the drug's solid state, FTIR spectroscopy, DSC, and XRD analyses were conducted. Microscopic examination unveiled that EC-based fibres exhibited homogeneity and lacked bead formations, albeit with larger diameters than other formulations. In contrast, both EC and PVA-based fibres displayed bead formations and nanometer-scale widths. The incorporation of penetration enhancers led to the production of uniform, bead-free nanofibers, with minor impacts on fiber size. EC fibres exhibited the lowest tensile strength and modulus of elasticity, but maximum flexibility. The addition of PVA and penetration enhancers contributed to enhanced fibre toughness and resistance to deformation. These alterations also positively influenced drug release rates, as observed in experiments conducted on cellophane membranes. Notably, when comparing drug release on rat skin to cellophane membranes, a slower initial release followed by a steeper slope was noted, attributed to the beneficial role of penetration enhancers on skin permeation. Analyzing results from DSC revealed the transition of the crystalline form of diclofenac diethylamine to an amorphous state within the nanofiber matrix which was also supported by XRD data. In light of these findings, electrospun nanofibers comprising a combination of EC and PVA polymers, alongside a penetration enhancer and diclofenac diethylamine, exhibit considerable promise for utilization as transdermal patches.

Formulation Development and In vitro Permeability of Curcumin Films Using Different Penetration Enhancers

Objective: The objective of the present work was to develop curcumin transdermal films by solvent evaporation technique using Carboxy polymethylene and Eudragit RS 100 as matrix polymers. The influence of penetration enhancers: dimethyl sulphoxide (1, 2 and 3% (w/w)), tween 80 (1, 2 and 3% (w/w)) and oleic acid (1, 2 and 3% (w/w)) on the in vitro percutaneous absorption of Curcumin through the rabbit skin was evaluated. Methods: Differential scanning calorimetry was used to evaluate the compatibility between the drug and excipients. All the prepared formulations were evaluated for moisture content, moisture uptake, flatness, tensile strength, drug content determination and in vitro permeation studies across rabbit skin. Results: The enhancing effectiveness of the enhancers decreased in the order: Oleic acid > Dimethyl sulphoxide > Tween 80. Compared to the control formulation 1.3-fold enhancement was observed with 2% tween 80. There were no significant promoting effects at low concentrations of dimethyl sulphoxide; however, a 1.18-fold increase in Curcumin flux resulted in higher percentage (3%) of dimethyl sulphoxide. The highest enhancement factor was 1.43 with 2% oleic acid. The skin irritation tests showed negligible erythema and edema. Conclusion: The results suggested the possibility of using formulated curcumin films in topical conditions like wound healing. Keywords: Curcumin, carboxy polymethylene, eudragit RS 100, dimethyl sulphoxide, tween 80, oleic acid.

Nano-thermal imaging of the stratum corneum and its potential use for understanding of the mechanism of skin penetration enhancer

Nano-thermal analysis (nano-TA) is a localised thermal technique which maps a surface in terms of thermal transitions by combining atomic force microscopy with the use of thermal probes, allowing a spatial resolution of sub–100nm. In this communication, we describe the application of a localised nano-TA approach, transition temperature microscopy (TTM), to investigate the thermotropic properties of porcine stratum corneum (PSC) as a function of depth and the influence of penetration enhancer on the nano-thermal properties of PSC. The investigations were conducted on PSC removed using tape strips. The transition temperature of PSC recorded at ∼220°C was ascribed to protein denaturation/degradation. A decrease in the transition temperature was observed with an increase of skin depth. ‘Transition depression’ was observed when PSC was treated with propylene glycol, suggesting its water extraction effect on SC protein and a drop in the biomechanical properties of the SC. TTM has the potential to be extended to on in situ investigations of various penetration enhancers.

Influence of penetration enhancers and molecular weight in antifungals permeation through bovine hoof membranes and prediction of efficacy in human nails

This work aimed to evaluate the effect of different substances on the permeation of geraniol through bovine hoof membranes. Different penetration enhancers were able to increase the permeability up to 25 times compared to control. It was demonstrated that acetilcysteine in association with ascorbic acid increased the permeation, even in acid formulations. In addition, some antifungal drugs were incorporated into a gel formulation of HPMC containing acetylcysteine 5% and ascorbic acid 0.2% and then the permeation coefficient through bovine hoof membranes was evaluated. The relationship between permeability and molecular weight was established for fluconazole, miconazole, terbinafine, butenafine, geraniol and nerol. Geraniol and nerol, the antifungals with lower molecular weight, had the better permeability results. Permeability coefficients for nail plates were estimated and geraniol demonstrated similar or even better efficacy index values against T. rubrum, T. menthagrophytes and M. canis compared with terbinafine and miconazole.

In vitro and in vivo influence of penetration enhancers in the topical application of celecoxib

Objective: We investigated the potential effects of oleic acid (OA) and glycerol monooleate (GMO) on the skin delivery of CXB.Methods: The influence of both OA and GMO (5.0% or 10.0%) on the in vitro skin permeability of CXB (2.0%) was evaluated using propylene glycol (PG) as a vehicle. Also the in vitro potential cytotoxicity and genotoxicity and in vivo assays (skin irritation in rabbits and topical anti-inflammatory activity by in mice) were conducted.Results: As expected, the amount of CXB that permeated through the skin was minimal, but drug retention on the viable skin (epidermis plus dermis) was higher in association with treatment with 5.0% OA or GMO compared to the control treatment, meaning that there was a localized effect of CXB in the skin. No formulation presented cytotoxic or genotoxic potential, suggesting safety for cutaneous application. In vivo skin irritation assays indicated that no formulation was irritating to the skin becomes its use possible for a prolonged time. In vivo anti-inflammatory experiments indicated that both edema and protein extravasation were inhibited with a maximum % inhibition of 53.5.0% and 61.0% for 5.0 % GMO, respectively, and 48.0% and 35.5% for 5.0% OA, respectively. Such formulations were able to inhibit around twofold the percentage of ear edema in mice compared to a commercial product reference diclofenac commercial formula.Conclusion: There is no topical formulation currently available that contains both CXB and 5.0% GMO or OA, suggesting them as potential adjuvants that improve the skin delivery of CXB.

Influence of penetration enhancer on drug permeation from volatile formulations

Previously we have reported the influence of supersaturation on the permeation of fentanyl across model membranes and skin. The findings indicated that the vehicle and, specifically its residence time in skin, influence the ability of the formulation to enhance membrane drug permeation. The aim of the present study was to probe the role of vehicle components on (trans)dermal drug delivery in more detail. To this end, three commonly used chemical penetration enhancers were selected for investigation namely, propylene glycol (PG), octyl salicylate (OSAL) and isopropyl myristate (IPM). A further objective was to clarify the mechanism of action of OSAL. Model spray formulations were prepared consisting of 10% (v/v) of individual enhancers in ethanol. Saturated and supersaturated systems were evaluated for their ability to promote fentanyl transport across human skin in vitro. Mass balance studies and determination of the extent of uptake of enhancers by skin were also conducted. The results indicated that increasing the degree of drug saturation (DS) does not promote drug permeation for formulations in PG but increasing drug DS did promote drug permeation for IPM and some OSAL systems. This probably reflects faster depletion of PG compared with IPM and OSAL. Non-linear modelling of the permeation data indicated that PG and IPM act to promote drug solubility in the membrane whereas OSAL appears to act as a skin penetration enhancer by increasing drug diffusivity in the skin.

SC lipid model membranes designed for studying impact of ceramide species on drug diffusion and permeation, Part III: Influence of penetration enhancer on diffusion and permeation of model drugs

The impact of the lipophilic penetration enhancer, oleic acid (OA), on the barrier properties of stratum corneum (SC) lipid model membranes was investigated based on diffusion and permeation studies of model drugs covering a broad range of lipophilicities. Diffusion and permeation experiments of urea, caffeine and diclofenac sodium were conducted using Franz-type diffusion cells. HPLC and capillary electrophoresis techniques were employed to analyze the amount of permeated drug. An incorporation of OA to the SC lipid model membranes did not change the relation between the diffusion and permeation behavior of model drugs presented previously for SC lipid model membranes without OA. The fastest rate of diffusion through SC lipid model membranes occurred in the case of the most hydrophilic drug, urea. In the case of permeation studies of caffeine and diclofenac sodium across SC lipid model systems, the permeability parameters were either equal or slightly larger in favor of the most lipophilic drug, diclofenac sodium. OA had a pronounced impact on the barrier properties of SC lipid model membranes. It caused the impairment of the barrier function of the SC lipid model membrane with Cer [AP] (phytosphingosine-based ceramide), however, surprisingly improved the barrier properties of the SC lipid model system with Cer [EOS] (sphingosine-based acylceramide).

Influence of penetration enhancers on in vitro transdermal permeation of L-tethrahydropalmatine

To study the effect of different penetration enhancers on the in vitro transdermal permeation of 1-tethrahydropalmatine (L-THP) through rat skin. Both natural and chemical synthesis penetration enhancers were applied singly or jointly to investigate the skin permeation rates of l-THP. The skin permeation profiles were evaluated by Valian-Chien permeation cells with isolated rat skin. HPLC-UV method was established to determine the concentration of l-THP in samples. As chemical synthesis penetration enhancer was used alone, 8% azone was observed to be the optimal penetration enhancer with the maximal penetration rate of 21.153 microg x cm(-20 x h(-1). Although 2% menthol crystal or 5% eucalyptus oil was effective as a natural penetration enhancer when used alone, the average penetration rate reached only half of that of 8% azone. The penetration potency of either menthol oil or menthol crystal combined with 8% azone was more effective than that of azone alone (P < 0.05). Either menthol oil or menthol crystal combined with 8% azone is effective on transdermal penetration of l-THP in vitro. There is significant synergistic effect when natural penetration enhancers combined with chemical synthesis penetration enhancers.

Influence of penetration enhancers on topical delivery of 5-aminolevulinic acid from bioadhesive patches

The inclusion of chemical penetration enhancers in a novel patch-based system for the delivery of 5-aminolevulinic acid (ALA) was examined in vitro and in vivo. Poor penetration of ALA has been implicated as the primary factor for low response rates achieved with topical ALA-based photodynamic therapy of thicker neoplastic lesions, such as nodular basal cell carcinomas. Several chemical permeation enhancers (dimethylsulfoxide, Labrafac CC, Labrafac PG and Labrafil M1944CS) were incorporated into bioadhesive patches tailored to deliver 19 mg ALA/cm(2). In-vitro depth penetration studies into excised porcine skin showed that high concentrations of ALA (>9 micromol/cm(3)) could be delivered to a depth of 1.875 mm. However, inclusion of permeation enhancers did not significantly increase ALA delivery, relative to the control (P > 0.05). In-vivo studies were in strong agreement with in-vitro results, with formulations containing chemical enhancers showing no improvement in delivery compared with the control. The patches designed in this work are suited to defineable ALA delivery without the need to immobilise patients for up to 6 h, as is common with the cream-under-occlusion approach. Overall, permeation enhancers were not found to markedly enhance the topical delivery of ALA. However, chemical penetration enhancers may have a greater effect on the delivery of more lipophilic ALA prodrugs, which are thought to primarily permeate the stratum corneum via the intercellular pathway.

Improvement in bioavailability of transdermally applied flurbiprofen using tulsi ( Ocimum sanctum) and turpentine oil

Penetration enhancing potential of tulsi and turpentine oil on transdermal delivery of flurbiprofen, a potent non-steroidal anti-inflammatory agent, was investigated. The transdermal permeation rate of flurbiprofen across the rat abdominal skin from binary solvent mixture composition of propylene glycol (PG):isopropyl alcohol (IPA) (30:70%, v/v) was 98.88 μg/cm 2/h, significantly higher than other binary solvent mixtures. The corresponding steady state plasma concentration, 0.71 μg/ml, was much lower than required steady state plasma concentration of 3–5 μg/ml. Hence influence of tulsi and turpentine oil in the optimized binary solvent mixture along with the increased drug load on the flurbiprofen permeation was evaluated. The magnitude of the flux enhancement factor with turpentine oil and tulsi oil was 2.4 and 2.0 respectively at 5% (v/v) concentration beyond which there was no significant increase in the flux. Addition of 2% (w/v) hydroxypropyl methylcellulose (HPMC), as a thickening agent, resulted in desired consistency for the fabrication of patch with insignificant effect on permeation rate of flurbiprofen. The reservoir type of transdermal patch formulation, fabricated by encapsulating the flurbiprofen reservoir solution within a shallow compartment moulded from polyester backing film and microporous ethyl vinyl acetate membrane, did not modulate the skin permeation of flurbiprofen through rat skin in case of turpentine formulations whereas flux of formulations with tulsi oil was significantly altered. The influence of penetration enhancer and solvents on the anatomical structure of the rat skin was studied. Enhancement properties exhibited by turpentine oil and tulsi oil in optimized binary solvent mixture were superior as compared to solvent treated and normal control groups with negligible skin irritation. The fabricated transdermal patches were found to be stable. The bioavailability of flurbiprofen with reference to orally administered flurbiprofen in albino rats was found to increase by 2.97, 3.80 and 5.56 times with transdermal patch formulation without enhancer, tulsi and turpentine oil formulations, respectively. The results were confirmed by pharmacodynamic studies in rat edema inflammation model.

Time of Erythema Onset after Application of Methyl Nicotinate Ointments as Response Parameter: Influence of Penetration Kinetics and Enhancing Agents

The time of erythema onset may be used as a response parameter for quantification of the cutaneous erythema response induced by methyl nicotinate. The vehicles light mineral oil (LMO; test) and medium chain triglycerides (MCT; standard) were compared with regard to the pharmacodynamic response. Moreover, the influence of penetration enhancers on the time of erythema onset was investigated under zero order penetration kinetics. The enhancers dimethyl sulfoxide, diethylene glycol monoethyl ether and three different glycerides in different concentrations were added to MCT as a standard vehicle. All preparations were applied to the forearms of volunteers under infinite dose conditions at different thermodynamic drug activity levels (0.2–3.2% of the saturation level) and different drug concentrations (0.051–0.816%), respectively. Different penetration kinetics do not influence data of erythema onset, as these data are comparable to those obtained under finite dose conditions (first order penetration kinetics). With regard to the penetration enhancers, a significantly enhanced penetration of methyl nicotinate could be observed only for diethylene glycol monoethyl ether and dimethyl sulfoxide. However, no significant difference between light mineral oil and MCT could be found with regard to penetration enhancement. The time of erythema onset is an easy and efficient parameter for quantification of the pharmacodynamic response caused by nicotinates.

Percutaneous Penetration of Methyl Nicotinate from Ointments Using the Laser Doppler Technique: Bioequivalence and Enhancer Effects

Laser Doppler flowmetry (LDF) may be used to quantify erythema response as a result of an increased cutaneous microcirculation induced by methyl nicotinate (MN). Bioequivalence of a test and a standard preparation (vehicles: light mineral oil and medium chain triglycerides, respectively) was confirmed according to the pilot study of the FDA Guidance for Industry "Topical dermatologic corticosteroids: In Vivo bioequivalence" applying the staggered application and synchronized removal method for one defined concentration. Furthermore, the influence of penetration enhancers (5% w/w Dimethylsulfoxide (DMSO) and 10% w/w diethylene glycol monoethyl ether) on MN penetration was investigated. It was shown that DMSO and diethylene glycol monoethyl ether altered cutaneous microcirculation and thus MN penetration in comparison to the standard formulation. However, true penetration enhancement could only be proved with diethylene glycol monoethyl ether resulting from an improved drug solubility in the skin which was confirmed by attenuated total reflectance fourier transform infrared spectroscopy (ATR-FTIR). Increased MN penetration by DMSO was only caused by thermodynamic effects, i.e. a decreased drug solubility in the vehicle.

Influence of penetration enhancers on the thermomechanical properties and peel strength of a poly(isobutylene) pressure sensitive adhesive

Influence of penetration enhancers on the thermomechanical properties and peel strength of a poly(isobutylene) pressure sensitive adhesive

Influence of penetration enhancers on the blanching intensity of betamethasone 17-benzoate

The influence of various potential lipophilic penetration enhancers on the blanching intensity of the model drug betamethasone 17-benzoate is examined with respect to the thermodynamic activity of the drug in the vehicle. The parameter of response is the relative intensity of blanching. The penetration enhancing effects of the vehicles are quantified using two different parameters. The first is the activity-standardized bioavailability factor determined from activity-response lines, which equals the enhancement ratio. The highest value found was 6.4. The second parameter is the activity-standardized vertical distance, that is the difference of the response of preparations with equal thermodynamic drug activity, determined from activity-response lines and from one-point measurements applying suspensions. Both penetration enhancement-describing parameters show a linear correlation with the solubility of the model drug in different vehicles. This requires a substantial penetration of the vehicles themselves to be able to act as cosolvents in the stratum corneum. Penetration enhancement by this mechanism is only possible if the drug shows differentiated affinities to lipophilic, stratum corneum-like vehicles. Betamethasone 17-benzoate formulations with low drug solubility, solutions as well as suspensions with a low amount of solid in the vehicles, show drug depletion effects.

The influence of penetration enhancers on the volume instilled of eye drops

The influence of the physicochemical properties of various penetration enhancers on the weight of drops dispensed from flexible plastic dropper bottles was examined. Two dropper tips with a different design were compared and the dropper bottle was held in the upright position (90° angle) or at a 45° angle. These two angles were chosen to simulate the manipulation of an eye dropper bottle by the patient. The surface tension of the penetration enhancer solutions was determined using the dynamic drop volume method. The dynamic surface tension values ranged from 65 to 30 mN/m. The lower the surface tension of the solution, the lower the weight of the drop delivered. Both the design of the dropper tip and the manipulation technique of the dropper bottle had a moderate to important influence on the drop weight. The relationship between the surface tension of the penetration enhancer solution instilled and the comfort of the patient was evaluated by an acceptability test based on answering a questionnaire. Penetration enhancers can be used to reduce the drop size of conventional ophthalmic solutions on condition that they do not elicit local irritation.

Influence of various penetration enhancers on the in vitro permeation of amino acids across hairless mouse skin

The influence of various penetration enhancers including propylene glycol, oleic acid, Azone ®, isopropyl myristate, valine, and nanoparticles on the permeation coefficient for the permeation of amino acids through hairless mouse skin as well as a dialysis membrane was assessed in vitro. The two different types of membranes were employed in order to distinguish between effects due to thermodynamic parameters and those due to barrier resistance. Furthermore, the influence of these penetration enhancers on the amount of amino acids remaining within the skin was determined. Oleic acid was found to be the most efficient enhancer for amino acids (enhancement factor (EF) of 176 for histidine) followed by Azone ® (EF of 45 for phenylalanine). All other penetration enhancers failed to exert any significant effect on the skin permeation of amino acids. The fact that the enhancement effects of oleic acid and Azone ® are not reversible and that the enhancers exhibited no influence with dialysis membranes clearly indicate that both penetration enhancers induce their effects on the basis of changes in skin morphology. Choosing arginine, histidine and phenylalanine as test permeants enabled a correlation between the enhancement effects and the degree of ionization of the test permeant. Histidine is the only amino acid which is unionized at pH 7.4 due to its isoelectric point. This might be the reason why the permeation enhancement induced by valine was only detectable with histidine, and not with the other two amino acids. Neither penetration enhancer resulted in any significant effect on the amount of the amino acid accumulated in the skin.

A Novel In-Vitro Model for Assessment of Buccal Absorption of Peptide Drugs and the Influence of Penetration Enhancers

A Novel In-Vitro Model for Assessment of Buccal Absorption of Peptide Drugs and the Influence of Penetration Enhancers