The architecture and composition of the stratum corneum make it a particularly effective barrier against the topical and transdermal delivery of hydrophilic molecules and ions. As a result, different ...strategies have been explored in order to expand the range of therapeutic agents that can be administered by this route. Iontophoresis involves the application of a small electric potential to increase transport into and across the skin. Since current flow is preferentially via transport pathways with at least some aqueous character, it is ideal for hydrosoluble molecules containing ionisable groups. Hence, the physicochemical properties that limit partitioning and passive diffusion through the intercellular lipid matrix are beneficial for electrically-assisted delivery. The presence of fixed ionisable groups in the skin (pI 4–4.5) means that application of the electric field results in a convective solvent flow (i.e., electroosmosis) in the direction of ion motion so as to neutralise membrane charge. Hence, under physiological conditions, cation electrotransport is due to both electromigration and electroosmosis—their relative contribution depends on the formulation conditions and the physicochemical properties of the permeant. Different mathematical models have been developed to provide a theoretical framework in order to explain iontophoretic transport kinetics. They usually involve solutions of the Nernst–Planck equation – using either the constant field (Goldman) or electroneutrality (Nernst) approximations – with or without terms for the convective solvent flow component. Investigations have also attempted to elucidate the nature of ion transport pathways and to explain the effect of current application on the electrical properties of the skin—more specifically, the stratum corneum. These studies have led to the development of different equivalent circuit models. These range from simple parallel arrangements of a resistor and a capacitor to the inclusion of the more esoteric “constant phase element”; the latter provides a better mathematical description of the “non-ideal” behaviour of skin impedance. However, in addition to simply providing a “mathematical” fit of the observed data, it is essential to relate these circuit elements to biological structures present in the skin. More recently, attention has also turned to what happens when the permeant crosses the epidermis and reaches the systemic circulation and pharmacokinetic models have been proposed to interpret data from iontophoretic delivery studies in vivo. Here, we provide an overview of mathematical models that have been proposed to describe (i) the effect of current application on the skin and the implications for potential iontophoretic transport pathways, (ii) electrotransport kinetics and (iii) the fate of iontophoretically delivered drugs once they enter the systemic circulation.
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This work developed minoxidil sulphate-loaded chitosan nanoparticles (MXS-NP) for targeted delivery to hair follicles, which could sustain drug release and improve the topical treatment of alopecia. ...Chitosan nanoparticles were obtained using low-molecular weight chitosan and tripolyphosphate as crosslink agent. MXS-NP presented a monomodal distribution with hydrodynamic diameter of 235.5±99.9nm (PDI of 0.31±0.01) and positive zeta potential (+38.6±6.0mV). SEM analysis confirmed nanoparticles average size and spherical shape. A drug loading efficiency of 73.0±0.3% was obtained with polymer:drug ratio of 1:1 (w/w). Drug release through cellulose acetate membranes from MXS-NP was sustained in about 5 times in comparison to the diffusion rate of MXS from the solution (188.9±6.0μg/cm2/h and 35.4±1.8μg/cm2/h). Drug permeation studies through the skin in vitro, followed by selective recovery of MXS from the hair follicles, showed that MXS-NP application resulted in a two-fold MXS increase into hair follicles after 6h in comparison to the control solution (5.9±0.6μg/cm2 and 2.9±0.8μg/cm2). MXS-loading in nanoparticles appears as a promising and easy strategy to target and sustain drug delivery to hair follicles, which may improve the topical treatment of alopecia.
Clobetasol propionate (CLO) is a potent glucocorticoid used to treat inflammation-based skin, scalp, and hair disorders. In such conditions, hair follicles (HF) are not only the target site but can ...also act as drug reservoirs when certain formulations are topically applied. Recently, we have demonstrated nanostructured lipid carriers (NLC) containing CLO presenting epidermal-targeting potential. Here, the focus was evaluating the HF uptake provided by such nanoparticles in comparison to a commercial cream and investigating the influence of different physical stimuli i.e., infrared (IR) irradiation (with and without metallic nanoparticles-MNP), ultrasound (US) (with and without vibration) and mechanical massage on their follicular targeting potential. Nanosystems presented sizes around 180 nm (PdI < 0.2) and negative zeta potential. The formulation did not alter skin water loss measurements and was stable for at least 30 days at 5 °C. Nanoparticles released the drug in a sustained fashion for more than 3 days and increased passively about 40 times CLO follicular uptake compared to the commercial cream. Confocal images confirmed the enhanced follicular delivery. On the one hand, NLC application followed by IR for heat generation showed no benefit in terms of HF targeting even at higher temperatures generated by metallic nanoparticle heating. On the other hand, upon US treatment, CLO retention was significantly increased in deeper skin layers. The addition of mechanical vibration to the US treatment led to higher follicular accumulation compared to passive exposure to NLC without stimuli. However, from all evaluated stimuli, manual massage presented the highest follicular targeting potential, driving more than double the amount of CLO into the HF than NLC passive application. In conclusion, NLC showed great potential for delivering CLO to HF, and a simple massage was capable of doubling follicular retention.
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•Skin barrier impairment does not increase iontophoretic transport per se.•Decreased EO and increased Cl- ion transport can reduce anodal EM of cations.•Decreased EO can facilitate ...cathodal iontophoresis of anions.•Effects are more complex for iontophoretic transport of proteins.
The effect of skin barrier impairment on the iontophoretic transport of low (acetaminophen (ACM), lidocaine (LD), ketorolac (KT)) and high molecular weight permeants, (cytochrome c (Cyt c) and ribonuclease T1 (RNase T1)), was evaluated using tape-stripping (TS) and fractional laser ablation for “large-scale” and “localized” barrier disruption. Interestingly, removal of the stratum corneum did not invariably lead to an increase in iontophoretic delivery of the permeants. Decrease of electroosmotic (EO) flow and facilitated transport of Cl- ions in the cathode-to-anode direction, which reduced cation electromigration (EM), both impacted cation delivery by anodal iontophoresis but the effects were partly offset by enhanced passive diffusion. Decrease in EO increased cathodal iontophoresis of KT but not that of RNase T1. Permeability coefficients confirmed the superiority of EM over EO for small molecules, LD > KT > ACM. A combination of fractional laser ablation and iontophoresis was advantageous for both positively and negatively charged small molecules as passive penetration was significantly enhanced. In conclusion, results demonstrated that (i) skin ablation prior to anodal iontophoresis decreased EO and EM but could be advantageous for delivery if the ablative technique enhanced passive penetration thereby compensating reduction of electrotransport and (ii) reduced EO favored cathodal electrotransport.
Iontophoresis is an active non-invasive drug delivery technique that can increase the transport of charged and neutral molecules into and across biological membranes. Most research to-date has ...focused on (per)cutaneous iontophoretic drug delivery. However, recent studies illustrate its potential for drug delivery to the eye: corneal iontophoresis may enable targeted topical therapy of intracorneal diseases, whereas transscleral iontophoresis may enable non-invasive intraocular drug delivery. Areas covered: We describe iontophoretic principles in the context of ocular delivery before providing a summary of recent preclinical studies involving transcorneal and transscleral iontophoresis in vitro and in vivo. Subsequently, an overview of clinical applications with special focus on the transcorneal iontophoresis of riboflavin for corneal cross-linking and transscleral iontophoresis of corticosteroids for the treatment of posterior segment diseases is provided. Expert opinion: The feasibility of using iontophoresis for ocular drug delivery has been demonstrated. Drug formulation development and the ability to design iontophoretic applicators will now determine its success in the clinic. The specificities of the ocular globe must be taken into account; in particular, its unique morphology, and the smaller surface area available for drug diffusion and the fact that it is more susceptible to irritation and less robust than the skin.
•The microemulsion has an ideal gelling temperature considering the ocular surface.•Such formulation enables the association of two drugs in the same product.•Microemulsion increased corneal delivery ...of moxifloxacin compared to control.•The formulation maintains betamethasone penetration even considering tear flow.
This article proposes an in situ gelling microemulsion for the ocular delivery of moxifloxacin (MOX) combined with betamethasone (BET) for use as a topical formulation throughout the postoperative period following eye surgery. Thermal analyses indicated compatibility between the drugs and the selected excipients. The microemulsion presented parameters that guarantee ocular tolerability: a droplet size of 28.0 ± 0.1 nm (polydispersity index = 0.11 ± 0.01), a zeta potential of −10.3 ± 0.1 mV, a pH of 7.1 ± 0.1, and osmolarity of 579.0 ± 9.4 mOsmol kg−1. The formulation had an ideal gelling temperature for the ocular surface (32.8 ± 0.9 °C), which allowed precise dosing due to its liquid state at storage temperatures. When the drugs’ release was assessed in vitro, the microemulsion was shown to prolong both drugs’ release compared with controls. Last, ex vivo drug penetration tests were performed in porcine corneas under static conditions (i.e., left in contact with the corneal surface) or with a simulated tear flow. In static conditions, the microemulsion increased MOX’s penetration into the cornea but decreased BET’s compared with the control. However, when the formulation was subjected to a simulated tear flow throughout its corneal application, the microemulsion made MOX’s penetration statistically similar to that in static conditions, which was 2–3 times (p less than 0.05) greater than that provided by the control, while maintaining the same BET penetration level as the control. Altogether, the proposed in situ gelling microemulsion seems to be a convenient, effective alternative for use following intraocular surgery.
The objective was to investigate the feasibility of using buccal iontophoresis for the simultaneous delivery of chemotherapeutic agents with a view to developing a new approach to treat head and neck ...cancers. Short duration cathodal iontophoresis of 5-fluorouracil (5-FU; 20mM) and leucovorin (LV; 10mM) at 1mA/cm2 for 10 or 20min from aqueous solution and a 2% hydroxyethyl cellulose gel at pH 7.6 was evaluated using bovine mucosa in vitro. Iontophoresis resulted in a statistically significant increase in the mucosal deposition of both drugs as compared to passive diffusion (Student's t-test, α=0.05); in each case, drug delivery was selective for deposition with no permeation being observed. After 20min of iontophoresis, there was an ∼8-fold enhancement for 5-FU (1.46±0.86 and 11.93±3.81μg/cm2, respectively) and a 3-fold increase for LV (8.31±2.44 and 25.08±6.89μg/cm2, respectively) when using aqueous solutions. The same trend was observed when the gel was applied for 10min; passive delivery of 5-FU from the gel resulted in non-detectable levels in the mucosa, while 4.62±1.76μg/cm2 were deposited in the mucosa following iontophoresis. Similarly, iontophoretic delivery of LV from the gel resulted in ∼3-fold higher deposition as compared to passive diffusion (6.71±1.36 and 21.12±9.94μg/cm2, respectively). No drug permeation was observed in either case. In conclusion, iontophoresis can be used for targeted topical delivery of chemotherapeutics to the buccal mucosa and may enable less invasive local therapy of head and neck cancers.
The number of drug molecules approved by the regulatory authorities for transdermal administration is relatively modest – less than two dozen. Many other therapies might benefit from the advantages ...offered by the transdermal route. That they have not already done so is due to the exceptional efficacy of the stratum corneum as a diffusional barrier and its remarkable ability to restrict molecular transport. As a result only extremely potent therapeutics possessing the necessary physicochemical properties can be delivered by passive diffusion across intact skin at pharmacologically relevent rates. This has led to the development of several delivery technologies that might be used to expand the range of medicinal agents that can be administered transdermally with the requisite delivery kinetics. There are essentially two approaches: (i) provide an improved driving force to increase the rate of transport (i.e., act on the molecule) or (ii) modify the properties of the microenvironment through which diffusion must occur (i.e., act on the stratum corneum). The challenge for the latter approach is to compromise the barrier in a reversible and relatively painless manner that minimises irritation, is practical for chronic conditions and has minimal risk of infection. Here, we review some of the physical methods that have been used to either transiently perturb the skin barrier or to provide additional driving forces to facilitate molecular transport with a particular focus on technologies that have either led to marketed products or have at least reached the clinical development stage.
FLU aqueous humor concentrations assessed by microdialysis in rabbits after the topical administration of the following: (i) poloxamer/chitosan in situ forming gel, (ii) chitosan solution, and (iii) ...aqueous solution.
Fungal keratitis is a serious disease that can lead to loss of vision. Unfortunately, current therapeutic options often result in poor bioavailability of antifungal agents due to protective mechanisms of the eye. The aim of this work was to evaluate the potential of a chitosan solution as well as an
in situ gel-forming system comprised of poloxamer/chitosan as vehicles for enhanced corneal permeation and sustained release of fluconazole (FLU). For this,
in vitro release and
ex vivo corneal permeation experiments were carried out as a function of chitosan concentration from formulation containing the chitosan alone and combined with the thermosensitive polymer, poloxamer. Microdialysis was employed in a rabbit model to evaluate the
in vivo performance of the formulations. The
in vitro release studies showed the sustained release of FLU from the poloxamer/chitosan formulation.
Ex vivo permeation studies across porcine cornea demonstrated that the formulations studied have a permeation-enhancing effect that is independent of chitosan concentration in the range from 0.5 to 1.5% w/w. The chitosan solutions alone showed the greatest
ex vivo drug permeation; however, the poloxamer/chitosan formulation presented similar
in vivo performance than the chitosan solution at 1.0%; both formulations showed sustained release and about 3.5-fold greater total amount of FLU permeated when compared to simple aqueous solutions of the drug. In conclusion, it was demonstrated that both the
in situ gelling formulation evaluated and the chitosan solution are viable alternatives to enhance ocular bioavailability in the treatment of fungal keratitis.
The aim of the present work was to obtain an ophthalmic delivery system with improved mechanical and mucoadhesive properties that could provide prolonged retention time for the treatment of ocular ...diseases. For this, an
in situ forming gel comprised of the combination of a thermosetting polymer, poly (ethylene oxide)–poly (propylene oxide)–poly (ethylene oxide) (PEO–PPO–PEO, poloxamer), with a mucoadhesive agent (chitosan) was developed. Different polymer ratios were evaluated by oscillatory rheology, texture and mucoadhesive profiles. Scintigraphy studies in humans were conduced to verify the retention time of the formulations developed. The results showed that chitosan improves the mechanical strength and texture properties of poloxamer formulations and also confers mucoadhesive properties in a concentration-dependent manner. After a 10-min instillation of the poloxamer/chitosan 16:1 formulation in human eyes, 50–60% of the gel was still in contact with the cornea surface, which represents a fourfold increased retention in comparison with a conventional solution. Therefore, the developed formulation presented adequate mechanical and sensorial properties and remained in contact with the eye surface for a prolonged time. In conclusion, the
in situ forming gel comprised of poloxamer/chitosan is a promising tool for the topical treatment of ocular diseases.
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