Transcutaneous electroporation mediated delivery of doxepin-HPCD complex: a sustained release approach for treatment of postherpetic neuralgia.

The electroporation mediated transdermal delivery (Protocol - 120 V, 10 ms, 30 pulses at 1 Hz with post pulse waiting period of 20 min) of doxepin using pure drug solution (PDS) and doxepin-hydroxypropyl-beta-cyclodextrin (HPCD) complex solution (CDS) was studied using porcine epidermis model. The stoichiometry of drug-HPCD inclusion complex was determined by differential scanning calorimetry (DSC). The amount of doxepin retained in the epidermis following electroporation did not differ significantly between PDS and CDS. When the drug loaded epidermis was subjected to "Release studies", doxepin release attained a plateau within approximately 2.5 days in case of PDS, whereas in case of CDS, doxepin release was prolonged up to 5 days. Mechanistic studies across the nonbiological barriers demonstrated that the slow dissociation of complex was responsible for sustained release of drug from the epidermis. Pharmacodynamic studies were carried out by electroporation mediated delivery of CDS and PDS in hairless rats. The analgesic effect of doxepin was prolonged in case of CDS as compared to PDS.

Transdermal drug delivery enhanced by low voltage electropulsation (LVE).

The efficiency of low voltage electropulsation (LVE) technique for delivery of drugs and macromolecules across the skin was investigated. The in vitro studies were carried out across the porcine epidermis in Franz diffusion cells using salicylic acid and fluorescein labeled Dextran of molecular weight 10,000 Da (FD10K). LVE enhanced the transport of salicylic acid and FD10K by approximately 4-fold and approximately 2-fold, respectively over the control. The potential application of LVE in transdermal drug delivery was studied in the case of lidocaine hydrochloride. The transport of lidocaine hydrochloride was enhanced by approximately 8-fold over the control. The transport enhancement by LVE was compared with that of 1 min and 20 min constant DC iontophoresis at 0.5 mA/cm(2). Iontophoresis applied for 1 min delivers equivalent electrical dose as that of LVE (50 ms pulses for 20 min at 1 Hz) in the current set up. The transport by application of iontophoresis for 1 min was significantly less than the control (passive diffusion for 20 min). However, the application of iontophoresis for 20 min (electrical dose approximately 20-fold more than that of LVE) resulted in comparable drug transport as that of LVE. It is evident from the results of this experiment that the transdermal delivery of drugs could be enhanced by LVE which is a rather mild technique than electroporation or iontophoresis.

A study on the effect of inorganic salts in transungual drug delivery of terbinafine.

OBJECTIVES: The poor success rate of topical therapy in nail disorders is mainly because of the low permeability of keratinized nail plates. This can be overcome by utilizing potent perungual drug penetration enhancers that facilitate the drug permeation across the nail plate. This study evaluated the efficacy of inorganic salts in enhancing the trans-nail permeation using a model potent antifungal agent, terbinafine hydrochloride. METHODS: Permeation studies were carried out across human cadaver nail in a Franz diffusion cell using terbinafine solution (1 mg/ml; pH 3). Preliminary studies were carried out to assess the effect of salts (0.5 M) on the terbinafine permeation into and through the nail. Further, the influence of salt concentration (0.25-3 M) on permeation, the mechanism for the enhancement and the suitability of developing a formulation were also studied. KEY FINDINGS: Terbinafine permeation (3-5 fold) through the nail and drug load (4-7 fold) in the nail were enhanced significantly when salts were used at 0.5 M concentration. Increase in salt concentration up to 1 M increased the permeation, which decreased with further increase in salt concentration (>1 M). Mechanistic studies revealed that the enhanced permeation by salts was mainly due to their ability to increase the nail hydration and also to increase the thermodynamic activity of the drug. The cumulative amount of terbinafine permeated at 24 h from the formulated gel (9.70 +/- 0.93 microg/cm(2)) was comparable with that of a solution (11.45 +/- 1.62 microg/cm(2)). CONCLUSIONS: Given the promising results from the permeation and drug load studies, it was concluded that inorganic salts could be used as potent transungual permeation enhancers.

Transcutaneous sampling of ciprofloxacin and 8-methoxypsoralen by electroporation (ETS technique).

The novel technique of transcutaneous sampling of drugs by electroporation was developed to study the dermatokinetics of ciprofloxacin and 8-methoxypsoralen. The selected drugs differ in their aqueous solubility and also with respect to the extent of protein binding. Ciprofloxacin (15mg/kg) was administered i.v. through tail vein, whereas 8-methoxypsoralen (5mg/kg) was given by oral administration, in hairless rats and the time course of drug concentration in the plasma was determined. Drug concentration in the dermal extracellular fluid (ECF) was determined by ETS and microdialysis sampling techniques. The extent of penetration into dermal ECF for ciprofloxacin and 8-methoxypsoralen was found to be approximately 19-32% and approximately 13-23%, respectively. The drug concentration in the dermal ECF determined by ETS and microdialysis did not differ significantly from each other and so as were the pharmacokinetic parameters. The results show that ETS can be utilized as a potential technique for sampling of drugs from the dermal ECF.

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.

OcuDrain-E-A noninvasive technique for reduction of intraocular pressure.

OcuDrain-E is a noninvasive technique in which electrical pulses are applied across the cornea to enhance the rate of transcorneal water evaporation (TCWE). In vitro studies were carried out with rabbit cornea mounted on a Franz diffusion cell. Application of 30 pulses each of 1millisecond (ms) duration at >or=40V/cm(2) decreased the corneal resistivity approximately 80% indicating permeabilization of the cornea. The corneal resistivity was almost completely recovered within 6h when the pulse voltage was <40V/cm(2). The average TCWE at 40V/cm(2) was significantly (approximately 39-fold) higher than the control (t-test, p<0.0001). Application of electrical pulses (40V-30 pulses-1ms-1Hz) across the cornea resulted in significant decrease in the intraocular pressure (IOP) in rabbits. The electrical protocol was well tolerated by the rabbits. Microscopic studies revealed that the applied electrical protocol did not cause any edema or detachment of the epidermal layers. The results of current investigation suggest that OcuDrain-E could be developed as a potential technique for the treatment of glaucoma in patients who respond poorly to drugs.

Dermal drug levels of antibiotic (cephalexin) determined by electroporation and transcutaneous sampling (ETS) technique.

The purpose of this project was to assess the validity of a novel Electroporation and transcutaneous sampling (ETS) technique for sampling cephalexin from the dermal extracellular fluid (ECF). This work also investigated the plausibility of using cephalexin levels in the dermal ECF as a surrogate for the drug levels in the synovial fluid. In vitro and in vivo studies were carried out using hairless rats to assess the workability of ETS. Cephalexin (20 mg/kg) was administered (i.v.) through tail vein and the time course of drug concentration in the plasma was determined. In the same rats, cephalexin concentration in the dermal ECF was determined by ETS and microdialysis techniques. In a separate set of rats, only intraarticular microdialysis was carried out to determine the time course of cephalexin concentration in synovial fluid. The drug concentration in the dermal ECF determined by ETS and microdialysis did not differ significantly from each other and so as were the pharmacokinetic parameters. The results provide validity to the ETS technique. Further, there was a good correlation ( approximately 0.9) between synovial fluid and dermal ECF levels of cephalexin indicating that dermal ECF levels could be used as a potential surrogate for cephalexin concentration in the synovial fluid.