Overcoming challenges in dermal and transdermal delivery of herbal therapeutics with polymeric microneedles.

Natural products are generally preferred medications owing to their low toxicity and irritancy potential. However, a good number of herbal therapeutics (HT) exhibit solubility, permeability and stability issues that eventually affect oral bioavailability. Transdermal administration has been successful in resolving some of these issues which has lead in commercialization of a few herbal transdermal products. Polymeric Microneedles (MNs) has emerged as a promising platform in transdermal delivery of HT that face problems in permeating the skin. Several biocompatible and biodegradable polymers used in the fabrication of MNs have been discussed. MNs have been exploited for cutaneous delivery of HT in management of skin ailments like skin cancer, acne, chronic wounds and hypertrophic scar. Considering the clinical need, MNs are explored for systemic delivery of potent HT for management of diverse disorders like asthma, disorders of central nervous system and nicotine replacement as it obviates first pass metabolism and elicits a quicker onset of therapeutic response. MNs of HT have found good number of aesthetic applications in topical delivery of HT to the skin. Interestingly, MNs have emerged as an attractive option as a minimally invasive diagnostic aid in sampling biomarkers from plants, skin and ocular interstitial fluid. The review updates the progress made by MN technology of HT for multiple therapeutic interventions along with the future challenges. An attempt is made to illustrate the challenging formulation strategies employed in the fabrication of polymeric MNs of HT. Efforts are on to extend the potential applications of polymeric MNs to HT for diverse therapeutic applications.

Development of silymarin topical formulation: In vitro and ex vivo dermal kinetics of silymarin.

Silymarin constituents are extensively investigated in the treatment of skin disorders. The main constituents of silymarin include taxifolin (TX), silychristin (ST), silydianin (SDN), silybin A (SA), silybin B (SB), isosilybin A (ISA) and isosilybin B (ISB). The objective of the present study was to determine in-vitro dermal kinetics of individual silymarin constituents in human skin models and to develop a silymarin topical formulation. In-vitro studies indicate human skin binding of silymarin was in the range of 2.09 to 12.3% and half-life of silymarin constituents was > 15.5 h in epidermal and dermal cells. Topical silymarin cream was prepared using sulfobutylether-ß-cyclodextrins as solubilizer and propylene glycol as permeation enhancer. The cream was subjected to ex-vivo human skin permeation studies. In ex-vivo studies, cumulative amount of TX, ST, SDN, SA, SB, ISA and ISB permeated across human cadaver skin at 24 h was 921 ± 13.5, 1992 ± 67.6, 345 ± 39.2, 1089 ± 45.0, 1770 ± 100, 1469 ± 81.5 and 1285 ± 33.1 ng/cm2, respectively. The amount TX, ST, SDN, SA, SB, ISA and ISB retained after 24 h was 60.7 ± 8.2, 376 ± 45.5, 72.3 ± 6.9, 66.4 ± 8.0, 208 ± 31.3, 154 ± 12.4 and 102 ± 6.3 ng/mg of human cadaver skin, respectively. The study results demonstrate silymarin topical formulation could deliver significant amount of silymarin constituents into skin. The developed silymarin formulation could be beneficial for treatment or management of a broad spectrum of dermatological disorders.

Rapidly Dissolving Microneedle Patches for Transdermal Iron Replenishment Therapy.

The prevalence of iron deficiency anemia (IDA) is predominant in women and children especially in developing countries. The disorder affects cognitive functions and physical activity. Although oral iron supplementation and parenteral therapy remains the preferred choice of treatment, gastric side effects and risk of iron overload decreases adherence to therapy. Transdermal route is an established approach, which circumvents the side effects associated with conventional therapy. In this project, an attempt was made to investigate the use of rapidly dissolving microneedles loaded with ferric pyrophosphate (FPP) as a potential therapeutic approach for management of IDA. Microneedle array patches were made using the micromolding technique and tested in vitro using rat skin to check the duration required for dissolution/disappearance of needles. The ability of FPP-loaded microneedles to replenish iron was investigated in anemic rats. Rats were fed iron-deficient diet for 5 weeks to induce IDA following which microneedle treatment was initiated. Recovery of rats from anemic state was monitored by measuring hematological and biochemical parameters. Results from in vivo study displayed significant improvements in hemoglobin and serum iron levels after 2-week treatment with FPP-loaded microneedles. The study effectively demonstrated the potential of microneedle-mediated iron replenishment for treatment of IDA.

Transdermal Delivery of Iron Using Soluble Microneedles: Dermal Kinetics and Safety.

Currently, the iron compounds are administered via oral and parenteral routes in patients of all ages, to treat iron deficiency. Despite continued efforts to supplement iron via these conventional routes, iron deficiency still remains the most prevalent nutritional disorder all over the world. Transdermal replenishment of iron is a novel, potential approach of iron replenishment. Ferric pyrophosphate (FPP) was found to be a suitable source of iron for transdermal replenishment. The safety of FPP was assessed in this project by challenging the dermal fibroblast cells with high concentration of FPP. The cell viability assay and reactive oxygen species assay were performed. The soluble microneedle array was developed, incorporated with FPP and the kinetics of free iron in the skin; extracellular fluid following dermal administration of microneedle array was investigated in hairless rats. From the cell based assays, FPP was selected as one of the potential iron sources for transdermal delivery. The microneedles were found to dissolve in the skin fluid within 3 hours of administration. The FPP concentration in the dermal extracellular fluid declined after complete dissolution of the microneedle array. Overall, the studies demonstrated the safety of FPP for dermal delivery and the feasibility of soluble microneedle approach for transdermal iron replenishment therapy.

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.

Upregulation of endogenous neurotrophin levels in the brain by intranasal administration of carnosic acid.

The potential of intranasally administered carnosic acid to enhance the endogenous levels of neurotrophins [nerve growth factor and brain-derived neurotrophic factor] in the brain was investigated. Hydroxypropyl-ß-cyclodextrin (HP-ß-CD) was used to enhance the aqueous solubility of carnosic acid. The effect of different concentrations of chitosan on the permeation of carnosic acid was investigated across the bovine olfactory mucosa using Franz diffusion cell setup. The formulations were administered [intranasal (i.n.)/subcutaneous route] in Sprague-Dawley rats, and the neurotrophins were sampled from the brain by microdialysis after the treatment period and measured by enzyme-linked immunosorbent assay. Phase solubility studies revealed that the solubility of carnosic acid was enhanced significantly with increase in the concentration of HP-ß-CD. The neurotrophin levels were enhanced significantly upon i.n. administration of carnosic acid with chitosan, which was approximately 1.5-2-fold more over the parenteral route. Nose-to-brain delivery of carnosic acid along with chitosan is a potential approach for treating disorders associated with depletion of neurotrophins.

Enhancement of nose-brain delivery of therapeutic agents for treating neurodegenerative diseases using peppermint oil.

The nose-brain pathway is a potential route for drug delivery as it bypasses the brain barriers. The main objective of this study was to investigate the efficacy of peppermint oil in enhancing the bioavailability of intranasally administered neurotrophins like nerve growth factor (NGF). The effect of different concentrations of peppermint oil (PO) on the delivery of NGF across bovine olfactory epithelium was studied in vitro using Franz diffusion cells. Trans-olfactory epithelial electrical resistance (TEER) was measured to assess the permeability status of the bovine olfactory epithelium. The bioavailability of intranasally administered formulations in rat hippocampus was studied by carrying out brain microdialysis in male Sprague-Dawley rats. Peppermint oil at concentrations of 0.05, 0.1 and 0.5% v/v enhanced the in vitro transport of NGF by 5, 7 and 8 fold, respectively. In vivo studies employing brain microdialysis in rats demonstrated that intranasal administration of NGF formulation with 0.5% PO enhanced the bioavailability by approximately 8 fold compared to rats administered with NGF alone. The bioavailability of NGF in the brain could be enhanced by intranasal administration of peppermint oil.

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 (d(vm) = 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 T(max) (2 h), elevated C(max) (106.06 +/- 12.18 mug/dL) and increased AUC (0-16 h) (647.44 +/- 52.33 mug.h/dL) for these microspheres which significantly differed (P <0.05) from FPP solution indicating a higher iron repletion potential of the BSA microspheres.

Ungual and trans-ungual iontophoretic delivery of terbinafine for the treatment of onychomycosis.

The application of iontophoresis was demonstrated in the nail drug delivery of terbinafine (TH) recently. This study explored a systematic assessment of this approach to enhance the drug delivery using a novel topical formulation, and the subsequent release of TH from the drug loaded nails. For the first time, a nail on-agar plate model was used to study the release of drug from the iontophoresis (0.5 mA/cm(2)) loaded nails. In addition, the activity of the drug released from the drug loaded nail plate was studied against Trichophyton rubrum. An increase in applied current density and current duration enhanced the transport of TH into and through the nail plate. In vitro release of drug from the iontophoretic loaded nails into agar plates exhibited 2-phase release pattern. The amount of drug released in both of the in vitro models was comparable, and the nails loaded using iontophoresis continued to release levels of TH > 2 orders of magnitude above the minimum inhibitory concentration over at least 52 days. Results indicate that iontophoresis enhances the delivery of terbinafine into and through the nail plate and suggest that the use of this treatment approach could result in a safe and more efficacious outcome with less frequent treatments.

TranScreen-N: Method for rapid screening of trans-ungual drug delivery enhancers.

Topical monotherapy of nail diseases such as onychomycosis and nail psoriasis has been less successful due to poor permeability of the human nail plate to topically administered drugs. Chemical enhancers are utilized to improve the drug delivery across the nail plate. Choosing the most effective chemical enhancers for the given drug and formulation is highly critical in determining the efficacy of topical therapy of nail diseases. Screening the large pool of enhancers using currently followed diffusion cell experiments would be tedious and expensive. The main objective of this study is to develop TranScreen-N, a high throughput method of screening trans-ungual drug permeation enhancers. It is a rapid microwell plate based method which involves two different treatment procedures; the simultaneous exposure treatment and the sequential exposure treatment. In the present study, several chemicals were evaluated by TranScreen-N and by diffusion studies in the Franz diffusion cell (FDC). Good agreement of in vitro drug delivery data with TranScreen-N data provided validity to the screening technique. In TranScreen-N technique, the enhancers can be grouped according to whether they need to be applied before or simultaneously with drugs (or by either procedures) to enhance the drug delivery across the nail plate. TranScreen-N technique can significantly reduce the cost and duration required to screen trans-ungual drug delivery enhancers.