Formulation approaches to improving the delivery of an antiviral drug with activity against seasonal flu.

The main objective of the present study was to develop formulations of noscapine hydrochloride hydrate with enhanced solubility and bioavailability using co-solvent- and cyclodextrin-based approaches. Different combinations of co-solvents, which were selected on the basis of high-throughput solubility screening, were subjected to in vitro intestinal drug permeability studies conducted with Ussing chambers. Vitamin E tocopherol polyethylene glycol succinate and propylene glycol based co-solvent formulations provided the maximum permeability coefficient for the drug. Inclusion complexes of the drug were prepared using hydroxypropyl-ß-cyclodextrin and sulphobutylether cyclodextrins. Pharmacokinetic studies were carried out in male Sprague-Dawley rats for the selected formulations. The relative bioavailabilities of the drug with the co-solvent- and cyclodextrin-based formulations were found to be similar.

Iontophoresis across the proximal nail fold to target drugs to the nail matrix.

The main objective of the present study was to investigate the plausibility of iontophoretic delivery of drugs to the nail matrix via proximal nail fold. The in vitro drug transport studies were performed in Franz diffusion cells across folded epidermis, which is used as a model for the proximal nail fold. The amount of drug transported into the receiver compartment following iontophoresis for 3 h at 0.5 mA/cm(2) was 150-fold higher than the control (0.008 ± 0.002 µg/cm(2)). The amount of drug present in the skin after iontophoresis (0.45 ± 0.12 µg/mg) was approximately fivefold higher as compared with that of the control (0.08 ± 0.01 µg/mg). Iontophoresis of terbinafine across the proximal nail fold was assessed using excised cadaver toe model as well. A custom-designed foam-pad-type patch system was used for iontophoresis in cadaver toes. The amount of the drug delivered into the nail matrix following iontophoresis for 3 h was significantly higher than the minimum inhibition concentration of terbinafine. However, on the contrary, passive delivery for about 24 h did not result in any detectable drug levels in the nail matrix. Iontophoresis across the proximal nail fold could be developed as a potential method to target drugs to nail matrix.

Magnetophoresis in combination with chemical enhancers for transdermal drug delivery.

PURPOSE: The objective of the present work was to investigate the effect of combination of a novel physical permeation enhancement technique, magnetophoresis with chemical permeation enhancers on the transdermal delivery of drugs. METHODS: The in vitro drug transport studies were carried out across the freshly excised abdominal skin of Sprague-Dawley rats using transdermal patch systems (magnetophoretic and non-magnetophoretic) of lidocaine hydrochloride (LH). LH gel prepared using hydroxypropyl methylcellulose (HPMC) was spread over the magnets as a thin layer. To investigate the effect of chemical permeation enhancers, menthol, dimethyl sulfoxide, sodium lauryl sulfate and urea (5% w/v) were incorporated in the gels prior to loading on the patch system. RESULTS: The flux of lidocaine from magnetophoretic patch was ~3-fold higher (3.07 ± 0.43 µg/cm(2)/h) than that of the control (non-magnetophoretic patch) (0.94 ± 0.13 µg/cm(2)/h). Incorporation of chemical permeation enhancers in the gel enhanced the magnetophoretic delivery flux by ~4 to 7-fold. CONCLUSIONS: The enhancement factor due to combination of chemical permeation enhancer was additive and not synergistic. Mechanistic studies indicated that magnetophoresis mediated drug delivery enhancement was via appendageal pathway.

Magnetophoresis for enhancing transdermal drug delivery: Mechanistic studies and patch design.

Magnetophoresis is a method of enhancement of drug permeation across the biological barriers by application of magnetic field. The present study investigated the mechanistic aspects of magnetophoretic transdermal drug delivery and also assessed the feasibility of designing a magnetophoretic transdermal patch system for the delivery of lidocaine. In vitro drug permeation studies were carried out across the porcine epidermis at different magnetic field strengths. The magnetophoretic drug permeation "flux enhancement factor" was found to increase with the applied magnetic field strength. The mechanistic studies revealed that the magnetic field applied in this study did not modulate permeability of the stratum corneum barrier. The predominant mechanism responsible for magnetically mediated drug permeation enhancement was found to be "magnetokinesis". The octanol/water partition coefficient of drugs was also found to increase when exposed to the magnetic field. A reservoir type transdermal patch system with a magnetic backing was designed for in vivo studies. The dermal bioavailability (AUC(0-6h)) from the magnetophoretic patch system in vivo, in rats was significantly higher than the similarly designed non-magnetic control patch.

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.

"ChilDrive": a technique of combining regional cutaneous hypothermia with iontophoresis for the delivery of drugs to synovial fluid.

PURPOSE: Bioavailability of drugs in the synovial fluid when administered via transdermal route is highly limited due to the dermal clearance. The purpose of this project was to assess the efficiency of ChilDrive (CD) technique to improve the drug targeting to the synovial fluid. CD is a technique of transdermal delivery of drugs combining regional hypothermia and iontophoresis. METHODS: Diclofenac sodium and Prednisolone sodium phosphate were administered by transdermal route (Passive, Iontophoresis, Chil-Passive and ChilDrive) at the knee-joint region of hind limb in sprague dawley rats for 6 h. Intraarticular microdialysis was carried out to determine the time course of drug concentration in the synovial fluid. Drug levels in synovial fluid after intravenous and intraarticular administration were also determined. RESULTS: Iontophoretic delivery increased the AUC(0-t) (area under the curve) of drugs in the synovial fluid by 3-fold over passive delivery (0.86 +/- 0.04 and 2.0 +/- 0.06 microg.h/ml for diclofenac sodium and prednisolone sodium phosphate, respectively). CD resulted in an AUC(0-t) of 5.2 +/- 0.69 and 24.6 +/- 1.97 microg.h/ml for diclofenac sodium and prednisolone sodium phosphate which was approximately 6-12-fold higher than the passive and 2-4-fold higher than iontophoresis. CONCLUSIONS: The results support our hypothesis that CD improves bioavailability of drugs to the synovial joints. CD could be developed as a potential noninvasive technique for treatment of arthritis.

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.

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.