H.N. Shivakumar

Ungual and Transungual drug delivery

Topical therapy is desirable in treatment of nail diseases like onychomycosis (fungal infection of nail) and psoriasis. The topical treatment avoids the adverse effects associated with systemic therapy, thereby enhancing the patient compliance and reducing the treatment cost. However the effectiveness of the topical therapies has been limited due to the poor permeability of the nail plate to topically applied therapeutic agents. Research over the past one decade has been focused on improving the transungual permeability by means of chemical treatment, penetration enhancers, mechanical and physical methods. The present review is an attempt to discuss the different physical and chemical methods employed to increase the permeability of the nail plate. Minimally invasive electrically mediated techniques such as iontophoresis have gained success in facilitating the transungual delivery of actives. In addition drug transport across the nail plate has been improved by filing the dorsal surface of the nail plate prior to application of topical formulation. But attempts to improve the trans-nail permeation using transdermal chemical enhancers have failed so far. Attempts are on to search suitable physical enhancement techniques and chemical transungual enhancers in view to maximize the drug delivery across the nail plate.

Bilayered Nail Lacquer of Terbinafine Hydrochloride for Treatment of Onychomycosis

The present study aimed to develop bilayered nail lacquer of terbinafine hydrochloride (TH) for treatment of onychomycosis. The composite nail lacquer formed an underlying drug-loaded hydrophilic layer and overlying hydrophobic vinyl layer. The hydrophilic lacquer made of hydroxylpropyl methylcellulose E-15 contained polyethylene glycol 400 (PEG 400) as a drug permeation enhancer. The vinyl lacquer was composed of poly (4-vinyl phenol) as a water-resistant film former. In vitro permeation studies in Franz diffusion cells indicated that the amount of TH permeated across the human cadaver nail in 6 days was 0.32 +/- 0.14, 1.12 +/- 0.42, and 1.42 +/- 0.53 microg/cm(2) from control (hydrophilic lacquer devoid of PEG 400), monolayer (hydrophilic lacquer alone), and bilayered nail lacquers, respectively. A higher nail drug load was seen in vitro with the bilayered lacquer (0.59 +/- 0.13 microg/mg) as compared to monolayer (0.36 +/- 0.09 microg/mg) and control (0.28 +/- 0.07 microg/mg) lacquers. The drug loss despite multiple washing was significantly low (p < 0.001) for the bilayered lacquer owing to the protective vinyl coating. Clinical studies demonstrated the efficacy of bilayered lacquer to achieve better drug load in the nail plate (1.27 +/- 0.184 microg/mg) compared to monolayer (0.67 +/- 0.18 microg/mg) and control (0.21 +/- 0.04 microg/mg) lacquers.

Topical and Transdermal Drug Delivery

Publisher Summary This chapter discusses the topical and transdermal drug delivery systems. The human stratum corneum acts as a barrier for the permeation of a number of active substances. This has limited the number of molecules commercially available as transcutaneous delivery systems. Various strategies have been employed over the past few decades to optimize drug delivery across the skin. Approaches based on supersaturation, eutectic mixtures, prodrugs, and ion pairing have been used with success to improve the transdermal delivery of several poorly permeable compounds. Liposomes have been used as carriers of steroids, antifungals, and vaccines for cutaneous delivery. A substantial database has been generated on chemical penetration enhancers over the past few years, and the search for the ideal enhancers has been the prime focus of many research groups. The efficacy of a passive approach to enhance transdermal drug delivery is known to diminish with increasing size of the active substance. Therefore, the limited potential of these passive techniques to facilitate the delivery of macromolecules has given way to various device-based physical enhancement techniques such as iontophoresis, electoporation, sonophoresis, and microneedles. Iontophoresis is a technique that involves application of low-intensity electric current to skin to enhance the permeation of therapeutic agents. In spite of the emergence of several aggressive active enhancement methods, the demand for passive transdermal technologies to deliver smaller molecules continues to prevail. The prime reason for this is their safety and efficacy during long-term treatment, resulting in improved patient acceptance and compliance compared to the physical enhancement techniques.

Constant voltage 'Iron'tophoresis.

The objective of this study was to investigate the feasibility of rapid administration of iron via transdermal route as an alternative to parenteral route of administration. In vitro drug delivery studies were carried out using porcine epidermis mounted on Franz diffusion cells. The effect of chemical permeation enhancers and physical techniques (constant voltage iontophoresis, electroporation and combination of electroporation with iontophoresis) on the transport of ferric pyrophosphate (FPP) was studied. Transepidermal water loss (TEWL) and electrical resistance were measured in order to see the effect of these techniques on the skin barrier function. The amount of FPP permeated was not enhanced significantly with the use of any of the enhancers (P > 0.05). It was found that constant voltage iontophoresis (0.5, 2 or 4 V) for about 30 min across electroporated epidermis (120 V, 100 pulses, 10 ms at 5 Hz) enhanced the delivery of FPP over control in the range of 2- to 42-fold. Hence, a therapeutically required dose of iron could be delivered by transdermal route using electrically-mediated techniques.

Formulation and evaluation of carnosic acid nanoparticulate system for upregulation of neurotrophins in the brain upon intranasal administration

To develop formulations of carnosic acid nanoparticles and to assess their in vivo efficacy to enhance the expression of neurotrophins in rat model. Carnosic acid loaded chitosan nanoparticles were prepared by ionotropic gelation technique using central composite design. Response surface methodology was used to assess the effect of three factors namely chitosan concentration (0.1–1% w/v), tri-poly phosphate concentration (0.1–1% w/v) and sonication time (2–10 min) on the response variables such as particle size, zeta potential, drug encapsulation efficiency and drug release. The neurotrophins level in the rat brain upon intranasal administration of optimized batch of carnosic acid nanoparticles was determined. The experimental values for the formulation were in good agreement with those predicted by the mathematical models. A single intranasal administration of the optimized formulation of carnosic acid nanoparticles was sufficient to result in comparable levels of endogenous neurotrophins level in the brain that was almost on par with four, once a day intranasal administration of solution in rats. The results clearly demonstrated the fact that nanoparticulate drug delivery system for intranasal administration of carnosic acid would require less number of administrations to elicit the required pharmacological activity owing to its ability to localize on the olfactory mucosal region and provide controlled delivery of carnosic acid for prolonged time periods.

Delivery of ziconotide to cerebrospinal fluid via intranasal pathway for the treatment of chronic pain.

The purpose of the current study was to investigate the plausibility of delivery of ziconotide to the cerebrospinal fluid (CSF) via intranasal administration. Ziconotide was administered either in the form of solution or Kolliphor P 407 gels (KP 407) intranasally in Sprague-Dawley rats. The effect of incorporation of chitosan in the formulation was also investigated. Time course of drug in the CSF was investigated by collecting CSF from cisterna magna. Pharmacokinetics of ziconotide in CSF following intrathecal and intravenous (i.v.) administration of ziconotide was investigated. Upon intrathecal administration the elimination rate constant of ziconotide in CSF was found to be 1.01±0.34h(-1). The Cmax and Tmax of ziconotide in CSF following intravenous administration were found to be 37.78±6.8ng/mL and ~2h respectively. The time required to attain maximum concentration (Tmax) in CSF was less upon intranasal administration (15min) compared to i.v. administration (120min). Presence of chitosan enhanced the overall bioavailability of ziconotide from intranasal solution and gel formulations. The elimination rate constant of ziconotide in CSF following intranasal and intravenous administration of ziconotide solution was found to be 0.54±0.08h(-1) and 0.42±0.10h(-1) respectively. Whereas, intranasal administration of ziconotide in the form of in situ forming gel lowered the elimination rate significantly. These results suggest that intranasal administration could be a potential noninvasive and patient compliant method of delivering ziconotide to CSF to treat chronic pain.

Iontophoresis for drug delivery into the nail apparatus: exploring hyponychium as the site of delivery

Abstract In present studies, a hyponychium pathway (from ventral side of the nail plate) was investigated as a potential route of drug delivery into the nail apparatus using iontophoresis as an active physical method. In vitro transport studies were performed across the human nail plate using sodium fluorescein as a marker substrate for 24 h. After transport studies, the amount of sodium fluorescein extracted from an active diffusion area of the nail plate in case of iontophoresis was found to be ∼54-folds more to that of passive. The amount of sodium fluorescein retained in the peripheral area of the nail plate after application of iontophoresis was found to be ∼30-folds more relative to passive. Ex vivo transport studies were performed on excised human cadaver toe using terbinafine hydrochloride as a model drug for three days (8 h/day). The amount of terbinafine retained in the nail plate after application of iontophoresis (3.43 ± 1.34 µg/mg) was ∼20-folds more when compared with passive (0.17 ± 0.10 µg/mg). The amount of drug extracted from the nail bed and nail matrix was 1.73 ± 0.12 µg/mg and 0.55 ± 0.22 µg/mg, respectively. On the other hand, there was no detectable amount of terbinafine found in the nail bed and nail matrix in case of control (passive delivery). These studies show that the iontophoretic drug delivery through hyponychium region to other parts of the nail apparatus could be a potential way of onychomycosis treatment.

Transungual drug delivery: an update

Topical therapy continues to be the treatment of choice for the patients and clinicians in treating certain infections of the nails. Topical treatment is widely accepted as an adjunct with oral therapy to improve the cure rates, reduce the treatment duration, cut down the treatment cost and enhance the therapeutic outcomes. However, effectiveness of topical therapy continues to pose a challenge owing to the poor permeability of the nail plate to many therapeutic agents and the prolonged treatment periods. Research over the past one decade has been focused to improve the transungual permeation using chemical penetration enhancers, mechanical methods and physical methods. Disrupting the dorsal surface of the nail by treating with penetration enhancers or etching agents or abrasion or filing of the nail plate has proved to drastically improve the efficacy of topical therapy. The present review is an effort to update the different chemical enhancers and etching agents used to enhance the transungual permeability.

Effect of Terpenes on Transdermal Iontophoretic Delivery of Diclofenac potassium under Constant Voltage

Abstract Objective: The aim of the study was to enhance the transdermal delivery of diclofenac potassium (DP) from hydrogels by constant voltage iontophoresis (CVI). The other objective was to establish the safety and efficacy of CVI in rats. Materials and methods: Hydrogels of DP were developed using hydroxyethyl cellulose as matrix material and geraniol, l-menthol and thymol as iontophoretic efficiency enhancers (IEE). In vitro permeation of hydrogels under CVI (1.5 V) was performed in Franz diffusion cells across porcine skin. The ability of CVI to deliver therapeutic amount of DP in vivo was assessed in rat paw edema model. Results: CVI significantly (p < 0.05) increased the steady state flux of DP compared to the passive. The hydrogels containing geraniol and l-menthol enhanced the iontophoretic flux of DP by ∼4.75 and ∼4.49 fold, respectively compared to passive control. The in vivo studies indicated that CVI in combination with IEE, significantly reduced (p < 0.05) area under the curve (AUC) of % inflammation compared to passive treatment. An excellent correlation (r = 0.996) was noted between in vitro flux values and AUC of % inflammation. Conclusion: The preclinical studies conclusively demonstrated that CVI in combination with IEE’s such as geraniol or l-menthol has the potential to safely deliver therapeutic amounts of DP.

Albumin microspheres for oral delivery of iron

Bovine serum albumin (BSA) microspheres of ferric pyrophosphate (FPP) intended for passive targeting to the Peyer’s patches has been proposed for oral iron supplementation. Microspheres prepared by emulsification chemical cross linking method were characterized for surface topography, entrapment efficiency, particle size, particle charge and in vitro drug release. Microspheres of batch C with FPP to BSA ratio of 1:5 were found to be most suitable for targeting as they exhibited high entrapment (83.88 ± 4.31), high monodispersity (span = 1.24 ± 0.01), and least particle size (dvm = 4.40 ± 0.01). In addition the amount of iron retained in these microspheres despite exposure to simulated gastrointestinal conditions for 5 h was found to be 83.72 ± 4.22%, the highest in the three batches. The in vivo serum iron profiles in normal rats following oral administration displayed a reduced Tmax (2 h), elevated Cmax (106.06 ± 12.18 μg/dL) and increased AUC 0–16 h (647.44 ± 52.33 μg.h/dL) for these microspheres which significantly differed (P <0.05) from FPP solution indicating a higher iron repletion potential of the BSA microspheres.