S. Narasimha Murthy

Delivery of nerve growth factor to brain via intranasal administration and enhancement of brain uptake.

The main objective of the study was to investigate the efficacy of chitosan to facilitate brain bioavailability of intranasally administered nerve growth factor (NGF). In vitro permeability studies and electrical resistance studies were carried out across the bovine olfactory epithelium using Franz diffusion cells. The bioavailability of intranasally administered NGF in rat hippocampus was determined by carrying out brain microdialysis in Sprague-Dawley rats. The in vitro permeation flux across the olfactory epithelium of NGF solution without chitosan (control) was found to be 0.37 +/- 0.06 ng/cm(2)/h. In presence of increasing concentration of chitosan (0.1%, 0.25%, and 0.5%, w/v) the permeation flux of NGF was found to be 2.01 +/- 0.12, 3.88 +/- 0.19, and 4.12 +/- 0.21 ng/cm(2)/h respectively. Trans-olfactory epithelial electrical resistance decreased approximately 34.50 +/- 4.06% in presence of 0.25% (w/v) chitosan. The C(max) in rats administered with 0.25% (w/v) chitosan and NGF was 1008.62 +/- 130.02 pg/mL, which was significantly higher than that for rats administered with NGF only 97.38 +/- 10.66 pg/mL. There was approximately 14-fold increase in the bioavailability of intranasally administered NGF with chitosan than without chitosan. Chitosan can enhance the brain bioavailability of intranasally administered NGF.

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.

Trans-ungual iontophoretic delivery of terbinafine

Successful treatment of deep-seated nail infections remains elusive as the delivery of efficacious levels of antifungal drug to the site of action is very difficult. The aim of the present study was to attain rapid trans-ungual delivery of an antifungal agent, terbinafine, via the topical route using iontophoresis. Initial studies revealed that application of current (0.5 mA/cm(2)) could significantly enhance the trans-ungual delivery of terbinafine. An increase in the applied current or duration of current application enhanced the trans-ungual delivery of terbinafine. Permeation of terbinafine through the nail and drug load in the nail correlated well with the applied electrical dose. Release of drug from nails loaded using iontophoresis followed a two-phase release profile. Light microscopy studies substantiated the capability of iontophoresis to drive a charged molecule across the nail plate. The results of these studies indicate that iontophoresis could be developed as a potential technique for onychomycosis therapy.

Physical and chemical permeation enhancers in transdermal delivery of terbutaline sulphate.

ConclusionsThe efficacy of a magnetic field to act as a permeation enhancer was demonstrated. Because in vitro and in vivo performance of F1 and F2 were comparable, the substitution of chemical enhancers by magnetic field in transdermal delivery systems appears to be possible.

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.

Transungual delivery of terbinafine by iontophoresis in onychomycotic nails

Trans-nail permeability is limited due to the innate nature of the nail plate and the recent investigations indicated the potential of iontophoresis in enhancing the transungual drug delivery in normal nails. However, the onychomycotic nails differ from the normal nails with respect to the anatomical and biological features. The current study investigated the effect of iontophoresis (0.5 mA/cm2 for 1 h) on the transungual delivery of terbinafine in onychomycotic finger and toe nails. The presence of fungi in the onychomycotic nails was diagnosed by potassium hydroxide (KOH) microscopy. Passive and iontophoretic delivery of terbinafine across the infected nail was studied in Franz diffusion cell. Further, the release profile of terbinafine from the drug-loaded nails was investigated by agar diffusion method. KOH microscopy confirmed the presence of fungi in all the nails used. The amount of drug permeated across the nail plate was enhanced significantly during iontophoresis over passive delivery, that is, by 21-fold in case of finger and 37-fold in case of toe nails. Further, the total drug load in the onychomycotic nail was enhanced by ~12-fold (in both finger and toe nails) due to iontophoresis. Release of terbinafine from the iontophoresis-loaded nails into agar plates exhibited two phases, a rapid phase followed by a steady release, which extended >2 months. This study concluded that the drug delivery in onychomycotic nails did not differ significantly when compared with normal nails, although the extent of drug permeation and drug load differs between finger and toe nails.

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.

Alteration of the diffusional barrier property of the nail leads to greater terbinafine drug loading and permeation.

The diffusional barrier property of biological systems varies with ultrastructural organization of the tissues and/or cells, and often plays an important role in drug delivery. The nail plate is a thick, hard and impermeable membrane which makes topical nail drug delivery challenging. The current study investigated the effect of physical and chemical alteration of the nail on the trans-ungual drug delivery of terbinafine hydrochloride (TH) under both passive and iontophoretic conditions. Physical alterations were carried out by dorsal or ventral nail layer abrasion, while chemical alterations were performed by defatting or keratolysis or ionto-keratolysis of the nails. Terbinafine permeation into and across the nail plate following various nail treatments showed similar trends in both passive and iontophoretic delivery, although the extent of drug delivery varied with treatment. Application of iontophoresis to the abraded nails significantly improved (P<0.05) TH permeation and loading compared to abraded nails without iontophoresis or normal nails with iontophoresis. Drug permeation was not enhanced when the nail plate was defatted. Keratolysis moderately enhanced the permeation but not the drug load. Ionto-keratolysis enhanced TH permeation and drug load significantly (P<0.05) during passive and iontophoretic delivery as compared to untreated nails. Ionto-keratolysis may be more efficient in permeabilization of nail plates than long term exposure to keratolysing agents.

Noninvasive Transcutaneous Sampling of Glucose by Electroporation

Background: In people with diabetes, blood glucose levels should be monitored regularly to prevent serious complications associated with diabetes. This involves the invasive method of withdrawing blood, which causes inconvenience to patients. The objective of this study was to investigate the efficiency of the noninvasive electroporation and transcutaneous sampling (ETS) technique for predicting blood glucose levels. Methods: In vitro studies were carried out in Franz diffusion cells using porcine epidermis to assess the feasibility of transcutaneous sampling of glucose. In vivo, the ETS technique was assessed in the diabetes-induced Sprague—Dawley rat model. Glucose was sampled following the application of 30 electrical pulses of 1 ms duration at 120V/cm2, 1 Hz. Clarke error grid analysis was carried out for the venous blood glucose levels that were determined by the ETS with reference to those measured by a glucose meter. Results: The amount of glucose sampled by the ETS method both in vitro and in vivo was proportional to the dermal glucose concentration. All data points from in vivo studies were in A and B zones of Clarke error grid analysis, and the mean absolute relative error was 12.8%. Conclusion: Results of the present study demonstrate that ETS technique could be developed as a noninvasive method of predicting venous blood glucose levels in people with diabetes.

Formulation and Evaluation of Controlled-Release Transdermal Patches of Theophylline–Salbutamol Sulfate

Transdermal formulations containing theophylline and salbutamol sulfate (SS) were formulated using hydroxypropylmethylcellulose. Theophylline was loaded by adsorption with the aid of the coadsorbate sodium chloride. The formulations were subjected to in vitro release studies, and the dose of salbutamol and theophylline was optimized to yield the desired flux. The films were uniform and 93 ± 5.4 μm thick. The in vitro fluxes of theophylline and salbutamol sulfate from the formulation were 1.22 ± 0.4 mg/h/cm2 and 13.36 ± 1.02 μg/h/cm2, respectively. The formulation was subjected to pharmacodynamic studies in guinea pigs. The preconvulsive time (PCT) of guinea pigs increased significantly after 4 h, and the same was observed even after 24 h. Pharmacokinetic studies were carried out in healthy human volunteers. Theophylline was analyzed in saliva, and salbutamol was analyzed in the blood plasma. The Tmax of the drugs was 3 h, and appreciable concentrations of the drugs above their MEC could be analyzed even after 12 h. The elimination half-life of the drugs was significantly prolonged compared to that for tablets. There were no signs of erythema or edema in the volunteers during observation for a period of 7 days.