Pre-exposure prophylactic mucoadhesive sodium alginate microsphere laden pessaries for intravaginal delivery of tenofovir disoproxil fumarate.

The research aimed to develop novel bioadhesive sodium alginate (Na-Alg) microspheres laden pessaries for intravaginal delivery of tenofovir disoproxil fumarate (TDF), to overcome limitations of conventional dosage forms. Twelve batches of microspheres formulated by emulsification gelation method indicated that drug-polymer ratios and polymer type affected particle size, drug release, and entrapment efficiency (%EE). Microspheres of batch EH-8 with drug: polymer ratio of 1:4 containing equal amounts of Na-Alg and HPMC K100M displayed optimal %EE (62.09 ± 1.34 %) and controlled drug release (97.02 ± 4.54 % in 12 h). Particle size analysis in Matersizer indicated that microspheres (EH-8) displayed a surface-mean diameter of 11.06 ± 0.18 µm. Ex-vivo mucoadhesion studies on rabbit mucosa indicated that microspheres (EH-8) adhered well for 12 h. Microspheres integrated into pessaries displayed a sustained release profile (95.31 ± 1.37 % in 12 h) in simulated vaginal fluid. In vivo studies in rabbits indicated that pessaries displayed a significantly higher Cmax (41.18 ± 3.57 ng/mL) (P < 0.005) and reduced Tmax (1.00 ± 0.01 h) (P < 0.0001) of TDF concentrations in vaginal fluid compared to oral tablets. The microparticulate pessaries with the ability to elicit higher vaginal fluid levels in the crucial initial hours of insertion demonstrates a potential novel platform to offer better self-protection to HIV-negative women against HIV during sexual intercourse.

Development and optimization of in-situ gel containing chitosan nanoparticles for possible nose-to-brain delivery of vinpocetine.

Vinpocetine (VIN), a derivative of vincamine found in the vinca plant, widens blood vessels in the brain and has been shown to improve cognitive function, memory, and cerebrovascular disorders. Nevertheless, the clinical utility of VIN is constrained by factors such as low oral bioavailability owing to the first-pass metabolism that often demands frequent dosing of 3-4 tablets/day. In this regard, the present work aimed to develop VIN-loaded chitosan nanoparticles (VIN-CH-NPs) to surmount these limitations and in view to enhance delivery to the brain of VIN by minimizing systemic exposure. The chitosan (CH) nanoparticles (NP) were developed by ionotropic gelation technique employing tripolyphosphate (TPP) as a cross-linking agent. Employing Design of Experiments (DoE), the effect of CH and TPP concentrations and stirring speed were systematically optimized using Box Behnken design (BBD). The optimized batch of nanoparticles displayed a particle size, zeta potential, entrapment efficiency, and drug loading of 130.6 ± 8.38 nm, +40.81 ± 0.11 mV, 97.56 ± 0.04 %, and 61 ± 0.89 %, respectively. Fourier Transform Infrared Spectroscopy indicated the chemical integrity of the drug ruling out the interaction between the VIN and excipients used. DSC and PXRD data indicated that reduction of the crystallinity of VIN in the chitosan matrix. These VIN-CH-NPs manifested good stability, exhibiting an almost spherical morphology. To mitigate rapid mucociliary clearance upon intranasal administration, the optimized VIN-CH-NPs were incorporated into thermosensitive in situ gel (VIN-CHN-ISG). It was observed that the in-situ gel loaded with nanoparticles was opalescent with a pH level of 5.3 ± 0.38. It was also noted that the gelation temperature was 32 ± 0.89 °C, and the gelation time was approximately 15 s. The drug delivery to the brain through the nasal application of optimized VIN-NPs in situ gel was assessed in rats. The results indicated significant nasal application of the in-situ gel nearly doubled the Cmax (P < 0.05) and AUC0-t (P < 0.05) in the brain compared to oral administration. Nasal administration improved drug delivery to the brain by reducing systemic exposure to VIN. A histopathological study of the nasal mucosa revealed no irritation or toxicity, making it safe for nasal administration. These findings suggest that the developed NPs in-situ gel effectively targeted vinpocetine to the brain through the nasal pathway, providing a potential therapeutic strategy for managing Alzheimer's disease.

Polymer coated polymeric microneedles for intravitreal delivery of dexamethasone.

The polymer coated polymeric (PCP) microneedles (MNs) is a novel approach for controlled delivery of drugs (without allowing release of the excipients) to the target site. PCP MNs was explored as an approach to deliver the drug intravitreally to minimize the risks associated with conventional intravitreal injections. The core MNs was fabricated with polyvinyl pyrrolidone K30 (PVP K30) and coating was with Eudragit E100. Preformulation studies revealed that the films prepared using Eudragit E 100 exhibited excellent integrity in the physiological medium after prolonged exposure. FTIR studies were performed to investigate the possible interaction between the API and the polymer. The PCP MNs fabricated with different drug loads (dexamethasone sodium phosphate) were subjected to in vitro drug release studies. The drug release from uncoated MNs was instantaneous and complete. On the other hand, a controlled release profile was observed in case of PCP MNs. Likewise, even in the ex vivo porcine eye model, the drug release was gradual into the vitreous humor in case of PCP MNs. The uncoated microneedles released all the drug instantaneously where the PCP MNs retarded the release up to 3 h.

Continuous Manufacturing of Oil in Water (O/W) Emulgel by Extrusion Process.

Pharmaceutical industries and drug regulatory agencies are inclining towards continuous manufacturing due to better control over the processing conditions and in view to improve product quality. In the present work, continuous manufacturing of O/W emulgel by melt extrusion process was explored using lidocaine as an active pharmaceutical ingredient. Emulgel was characterized for pH, water activity, globule size distribution, and in vitro release rate. Additionally, effect of temperature (25°C and 60°C) and screw speed (100, 300, and 600 rpm) on the globule size and in vitro release rate was studied. Results indicated that at a given temperature, emulgel prepared under screw speed of 300 rpm resulted in products with smaller globules and faster drug release.

Polymer-Coated Polymeric (PCP) Microneedles for Controlled Dermal Delivery of 5-Fluorouracil.

Polymeric microneedles were prepared with Polyvinyl Pyrrolidone (PVP) K-30 using the mold casting technique. The core microneedles were coated with Eudragit E-100 by dip and spin method. The amount of 5-fluorouracil (FU) loaded in the core microneedles was 604 ± 35.4 µg. The coating thickness was 24.12 ± 1.12 µm. The objective was to deliver the 5-FU gradually in a controlled release manner at the target site in the sub-stratum corneum layer. This approach is anticipated to improve the safety and efficacy of topical melanoma treatment. The release of the drug was prolonged for up to 3 h from the polymer-coated polymeric (PCP) microneedles. The entire amount was found to release within 15 min in uncoated MNs. Likewise, the permeation of the drug from the uncoated microneedles was rapid, whereas the PCP microneedles were able to prolong the permeation up to 420 min. The PCP microneedles were subjected to stability studies at 25°C ± 2°C/60%RH, and 40°C ± 2°C/75%RH condition for 3 months. The formulations were found intact, and the release rate was not significantly different form the fresh formulation. The drug content was found to meet the acceptability criteria as well (98.12 ± 1.8% and 97.8 ± 2.1% at 25 and 40°C respectively after 3 months). Overall, this study demonstrated the feasibility of fabrication of PCP microneedles using Eudragit E100 for intraregional controlled delivery of drugs.

Polymer Coated Polymeric (PCP) Microneedles for Controlled Delivery of Drugs (Dermal and Intravitreal).

Microneedles are used to deliver drugs topically across the skin and mucous membranes. Dissolvable microneedles are made using soluble polymers, which disintegrates in the tissue and release the entire payload instantaneously including the polymer construct. Often, a slow release of drug into the tissue is desirable to overcome the severity of side effects at the site of administration as well as systemic adverse effects. In addition, controlled release of active pharmaceutical ingredient (API) only (not the excipients) is safe and effective particularly when the drug delivery is intended to sensitive organs like the eye. In this project, the feasibility of fabricating polymer coated polymeric (PCP) microneedles to achieve a gradual release of only the active ingredient from the device was investigated. The potential application of such PCP microneedles in the dermal and intravitreal drug delivery was also explored using animal tissue models. The PCP microneedles were found to be intact even after prolonged contact with the release medium. The time at which 50% (T50%) of dextran (10 K) was released in case of microneedles prepared using 20% of core polymer (PVP-K30) was about 15 min versus less than 5 min in the case of uncoated microneedles. Whereas when the core polymer concentration was increased to 50%, the T50% was increased to 90 min. The rate of release depended on the polymer molecular weight grade. The rate of drug release was not influenced by the total amount of concentration of dextran. The PCP microneedles of lidocaine hydrochloride could constantly release the drug for up to 9 h in the skin tissue. Likewise, the PCP microneedles infused voriconazole, intravitreally for 6 h.

Convective Solvent Transport Pathways for Absorption of Drugs from Topical Formulation.

Physicochemical and formulation factors influencing penetration of drugs from topical products into the skin and mechanisms of drug permeation are well investigated and reported in the literature. However, mechanisms of drug absorption during short-term exposure have not been given sufficient importance. In this project, the extent of absorption of drug molecules into the skin from aqueous and ethanolic solutions following a 5-min application period was investigated. The experiments demonstrated measurable magnitude of absorption into the skin for all the molecules tested despite the duration of exposure being only few minutes. Among the two solvents used, absorption was greater from aqueous than ethanolic solution. The results suggest that an alternative penetration pathway, herein referred to as the convective transport pathway, is likely responsible for the rapid, significant uptake of drug molecules during initial few minutes of exposure. Additionally, absorption through the convective transport pathways is a function of the physicochemical nature of the formulation vehicle rather than the API.

Polymer Coated Polymeric (PCP) microneedles for sampling of drugs and biomarkers from tissues.

The Polymer Coated Polymeric (PCP) microneedles were fabricated using PVP K30 in the core and ethyl cellulose in the coating. The PCP microneedles do not disintegrate in the tissue upon insertion and rather stays intact and allows diffusion of drugs and analytes across the membrane both inward and outward. In this project the potential use of PCP microneedles for sampling analytes from the dermal tissue was explored. The amount of analyte sampled depended on the concentration in the tissue, physicochemical properties of the analyte and duration of insertion of the array in the tissue. Further, an advanced type of PCP microneedle array was fabricated by entrapping absorbent beads in the core microneedles. The adsorbent enabled the PCP microneedles to recover significantly higher amount of analyte from the tissue.

Non-dermal applications of microneedle drug delivery systems.

Microneedles (MNs) are micron-scaled needles measuring 100 to 1000 µm that were initially explored for delivery of therapeutic agents across the skin. Considering the success in transcutaneous drug delivery, the application of microneedles has been extended to different tissues and organs. The review captures the application of microneedles to the oral mucosa, the eye, vagina, gastric mucosa, nail, scalp, and vascular tissues for delivery of vaccines, biologics, drugs, and diagnostic agents. The technology has created easy access to the poorly accessible segments of eye to facilitate delivery of monoclonal antibodies and therapeutic agents in management of neovascular disease. Microporation has been reported to drastically improve the drug delivery through the poorly permeable nail plate. Curved microneedles and spatially designed microneedle cuffs have been found to be capable of delivering stem cells and therapeutic macromolecules directly to the cardiac tissue and the vascular smooth muscle cells, respectively. Besides being minimally invasive and patient compliant, the technology has the potential to offer viable solutions to deliver drugs through impermeable barriers owing to the ability to penetrate several biological barriers. The technology has been successful to overcome the delivery hurdles and enable direct delivery of drug to the target sites, thus maximizing the efficacy thereby reducing the required dose. This review is an attempt to capture the non-dermatological applications of microneedles being explored and provides an insight on the future trends in the field of microneedle technology. Pictorial representation of different microneedle application.

Iontophoretic Mediated Intraarticular Delivery of Deformable Liposomes of Diclofenac Sodium.

BACKGROUND AND OBJECTIVE: Topical therapy is ineffective in the case of Musculoskeletal Disorders (MSD) as it is not able to maintain therapeutic levels of the drug in the affected joint due to its inability to surpass the dermal circulation and penetrate into deeper tissues. One of the approaches to enhance deep tissue penetration of drugs is to increase drug delivery much above the dermal clearance. The objective of the present work was to formulate negatively charged Deformable Liposomes (DL) of Diclofenac Sodium (DS) using biosurfactants and target the same to the synovial fluid by application of iontophoresis. METHODS: Deformable liposomes loaded with diclofenac sodium were formulated and characterized for surface morphology, particle size distribution, zeta potential and entrapment efficiency. In vitro permeation of the diclofenac from aqueous solution, conventional liposomes, and deformable liposomes under iontophoresis was performed using Franz diffusion cells and compared to passive control. Intraarticular microdialysis was carried out to determine the time course of drug concentration in the synovial fluid at the knee-joint region of the hind limb in Sprague Dawley rats. RESULTS: The vesicles were found to display a high entrapment (> 60%) and possess a negative zeta potential lower than -30 mV. The size of the vesicles was varied from 112.41 ± 1.42 nm and 154.6 ± 3.22 nm, demonstrated good stability on the application of iontophoresis. The iontophoretic flux values for the DS aqueous solution, conventional liposomes and deformable liposomal formulation were found to be 7.55 ± 0.42, 16.75±1.77and 44.01 ± 3.47 µg/ cm2 h-1, respectively. Deformable liposomes were found to display an enhancement of 5.83 fold compared to passive control. Iontophoresis was found to enhance the availability of DS deformable liposomes (0.56 ± 0.08 µg.h/ml) in the synovial fluid by nearly 2-fold over passive delivery (0.29 ± 0.05 µg.h/ml). CONCLUSION: Results obtained indicate that iontophoretic mediated transport of deformable liposomes could improve the regional bioavailability of diclofenac sodium to the synovial joints, an efficient mode for treating MSD in the elderly.

Effect of terpenes on transdermal iontophoretic delivery of diclofenac potassium under constant voltage.

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.

Development and evaluation of an oral fast disintegrating anti-allergic film using hot-melt extrusion technology.

The main objective of this novel study was to develop chlorpheniramine maleate orally disintegrating films (ODF) using hot-melt extrusion technology and evaluate the characteristics of the formulation using in vitro and in vivo methods. Modified starch with glycerol was used as a polymer matrix for melt extrusion. Sweetening and saliva-simulating agents were incorporated to improve palatability and lower the disintegration time of film formulations. A standard screw configuration was applied, and the last zone of the barrel was opened to discharge water vapors, which helped to manufacture non-sticky, clear, and uniform films. The film formulations demonstrated rapid disintegration times (6-11s) and more than 95% dissolution in 5min. In addition, the films had characteristic mechanical properties that were helpful in handling and storage. An animal model was employed to determine the taste masking of melt-extruded films. The lead film formulation was subjected to a human panel for evaluation of extent of taste masking and disintegration.

Trans-ungual Delivery of AR-12, a Novel Antifungal Drug.

AR-12 is a novel small molecule with broad spectrum antifungal activity. Recently, AR-12 was found to be highly active against Trichophyton rubrum, one of the predominantly responsible organisms that cause onychomycosis. The primary objective of this project was to investigate the ability of AR-12 to penetrate into and across the human nail plate followed by improving its trans-ungual permeation using different penetration enhancers. TranScreen-N™, a high throughput screening method was utilized to explore the potential nail penetration enhancers to facilitate the drug delivery through the nail. This screen demonstrated that dexpanthenol and PEG 400 were the most efficient enhancers. The in vitro permeation studies were performed across the human cadaver nail plates for 7 days with three AR-12 (5% w/v) formulations containing 10% w/v dexpanthenol (Formulation A), 10% w/v PEG 400 (Formulation B), and a combination of 10% w/v dexpanthenol + 10% w/v PEG 400 (Formulation C). The in vitro studies concluded that dexpanthenol and PEG 400 were able to deliver a significant amount of AR-12 into and across the nail plate that was found to be more than MIC 50 level of the drug.

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

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.

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.

Transdermal iron replenishment therapy.

Iron deficiency anemia is one of the major nutritional deficiency disorders. Iron deficiency anemia occurs due to decreased absorption of iron from diet, chronic blood loss and other associated diseases. The importance of iron and deleterious effects of iron deficiency anemia are discussed briefly in this review followed by the transdermal approaches to deliver iron. Transdermal delivery of iron would be able to overcome the side effects associated with conventional oral and parenteral iron therapy and improves the patient compliance. During preliminary investigations, ferric pyrophosphate and iron dextran were selected as iron sources for transdermal delivery. Different biophysical techniques were explored to assess their efficiency in delivering iron across the skin, and in vivo studies were carried out using anemic rat model. Transdermal iron delivery is a promising approach that could make a huge positive impact on patients suffering with iron deficiency.

Development of taste masked caffeine citrate formulations utilizing hot melt extrusion technology and in vitro-in vivo evaluations.

The objective of this study was to develop caffeine citrate orally disintegrating tablet (ODT) formulations utilizing hot-melt extrusion technology and evaluate the ability of the formulation composition to mask the unpleasant bitter taste of the drug using in vitro and in vivo methods. Ethylcellulose, along with a suitable plasticizer, was used as a polymeric carrier. Pore forming agents were incorporated into the extruded matrix to enhance drug release. A modified screw configuration was applied to improve the extrusion processability and to preserve the crystallinity of the API. The milled extrudates were subjected to dissolution testing in an artificial salivary fluid and investigations using e-tongue, to assess the extent of masking of bitter taste of the API. There was an insignificant amount of drug released from the formulation in the salivary medium while over 80% of drug released within 30 min in 0.1N HCl. ODTs were also developed with the extrudate mixed with mannitol and crospovidone. The quality properties such as friability and disintegration time of the ODTs met the USP specifications. The lead extrudate formulations and the ODTs prepared using this formulation were subjected to human gustatory evaluation. The formulations were found to mask the unpleasant taste of caffeine citrate significantly.

Formulation and evaluation of gemcitabine-loaded solid lipid nanoparticles.

Gemcitabine-loaded solid lipid nanoparticles (SLNs) were produced by double emulsification technique using stearic acid as lipid, soy lecithin as surfactant and sodium taurocholate as cosurfactant. Prepared nanoparticles are characterized for particle size and surface morphology using scanning electron microscopy (SEM). Particle yield, entrapment efficiency and zeta potential were also determined. In-vitro release studies were performed in phosphate-buffered saline (PBS) pH 7.4 using metabolic shaker. The formulation F6 with maximum entrapment efficiency 72.42% and satisfactory in-vitro release was selected. In-vivo tissue distribution to liver, spleen, lung, heart and kidneys of optimized formulation followed by stability study under specific conditions were also determined. This investigation has shown preferential drug targeting to liver followed by spleen, lungs, kidneys and heart. Stability studies showed no significant change in the particle size followed with very slight decrease in entrapment efficiency at 25 ± 2 °C/60 ± 5% RH over a period of three months.

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.

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.