Selection of Solid-State Plasticizers as Processing Aids for Hot-Melt Extrusion.

The objective of the study was to select solid-state plasticizers for hot-melt extrusion (HME) process. The physical and mechanical properties of plasticizers, in selected binary (polymer:plasticizer) and ternary (active pharmaceutical ingredient:polymer:plasticizer) systems, were evaluated to assess their effectiveness as processing aids for HME process. Indomethacin and Eudragit® E PO were selected as model active pharmaceutical ingredient and polymer, respectively. Solubility parameters, thermal analysis, and rheological evaluation were used as assessment tools. Based on comparable solubility parameters, stearic acid, glyceryl behenate, and polyethylene glycol 8000 were selected as solid-state plasticizers. Binary and ternary physical mixtures were evaluated as a function of plasticizer concentration for thermal and rheological behavior. The thermal and rheological assessments also confirmed the miscibility predictions from solubility parameters. The understanding of thermal and rheological properties of the various mixtures helped in predicating plasticization efficiency of stearic acid, glyceryl behenate, and polyethylene glycol 8000. The evaluation also provided insight into the properties of the final product. An empirical model was also developed correlating rheological property of physical mixtures to actual HME process. Based on plasticizer efficiency, solid-state plasticizers and processing conditions can be selected for a HME process.

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.

In vitro and in vivo evaluation of a hydrogel-based prototype transdermal patch system of alfuzosin hydrochloride.

The first-line therapy for moderate to severe benign prostatic hyperplasia is the oral therapy by alfuzosin hydrochloride. Unfortunately, the oral therapy of alfuzosin is associated with several route-specific systemic side-effects. The current study was aimed to develop a prototype transdermal patch system for alfuzosin using a hydrogel polymer and optimize the drug delivery through the skin for systemic therapy. The prospective of different chemical enhancers (polyethylene glycol (PEG 400), isopropyl myristate, propylene glycol, menthol and L-methionine; 5% w/v) and iontophoresis (0.3 mA/cm(2)) in the alfuzosin delivery across the full thickness rat skin was assessed in vitro. In vivo iontophoretic studies were carried out using selected patch system (PEG 400) for a period of 6 h in Sprague-Dawley rats. Passive permeation studies indicated that the incorporation of chemical agents have moderate effect (~4- to 7-fold) on the alfuzosin skin permeability and reduced the lag time. Combined approach of iontophoresis with chemical enhancers significantly augmented the drug transport (~ 43- to 72-fold). In vivo pharmacokinetic parameters revealed that the iontophoresis (transdermal patch with PEG 400) significantly enhanced the C(max) (~ 3-fold) and AUC(0-α) (~ 4-fold), when compared to control. The current study concludes that the application of iontophoresis (0.3 mA/cm(2)) using the newly developed agaorse-based prototype patch with PEG 400 could be utilized for the successful delivery of alfuzosin by transdermal route.

Delivery of brain-derived neurotrophic factor via nose-to-brain pathway.

PURPOSE: To investigate the plausibility of delivering brain-derived neurotrophic factor (BDNF) to brain via nose-to-brain pathway using chitosan as barrier-modulating agent. METHODS: Effect of different viscosity grades chitosan at different concentrations on permeation of fluorescein isothio-cyanate dextran (FD 40 K) across bovine olfactory mucosa was studied using Franz diffusion cells. Medium viscosity chitosan was used to carry out permeation studies of BDNF. Pharmacokinetic and pharmacodynamic studies were carried out in Sprague dawley rats upon intranasal/i.v administration of different formulations. RESULTS: Medium viscosity chitosan more efficiently enhanced permeation of FD 40 K across olfactory mucosa compared to other grades. In case of BDNF, medium viscosity chitosan (0.25% w/v) enhanced permeation ~14-fold over control (18.78 ± 16.69 ng/cm(2)). Brain bioavailability of rats administered intranasally with BDNF solution containing chitosan was significantly enhanced ~13-fold compared to rats administered with same concentration of BDNF solution without chitosan. In rats subjected to immobilization stress, BDNF solution containing chitosan significantly decreased immobility time. CONCLUSIONS: Intranasal formulations containing chitosan as barrier-modulating agent significantly enhanced brain bioavailability of BDNF. Delivery of BDNF was found to counteract stress-induced depression in rats.

Delivery of cefotaxime to the brain via intranasal administration.

The purpose of this study was to investigate the plausibility of delivery of cefotaxime to the brain via intranasal administration. In vitro permeation studies were carried out using Franz diffusion cells, and the effect of different concentrations of chitosan (0.1% w/v and 0.25% w/v) on drug permeation across the bovine olfactory mucosa was determined. Samples were collected from the receiver compartment at different time points and analyzed using HPLC. The amount of cefotaxime that permeated across the olfactory mucosa when 0.25% w/v of chitosan was used as a permeation enhancer was ~1.5- and ~2-fold higher at the end of the first hour and second hour, respectively, over control (29.56 ± 6.18 µg/cm(2)). There was no significant enhancement in drug permeation when 0.1% w/v chitosan was used as the permeation enhancer. Pharmacokinetic studies were carried out using Sprague-Dawley rats. Cefotaxime solution with 0.25% w/v chitosan (40 mg/kg) was administered intravenously (i.v.) to rats in groups 1 and 3 and intranasally to those in group 2 and 4. The time course of drug in the brain was investigated by performing microdialysis in rats of groups 1 and 2. Blood samples were withdrawn from rats in groups 3 and 4, and cefotaxime in plasma was analyzed using HPLC after extraction with a hydrochloric acid-chloroform:1-pentanol (3:1) and phosphate buffer solvent system. Pharmacokinetic parameters were calculated using the trapezoidal rule. The results imply that the drug levels attained in the brain following i.v. and intranasal administrations were comparable. These results suggest that intranasal administration of cefotaxime could be a potential method of delivering antibacterial agents because of it being noninvasive and patient compliant.

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/cm(2) 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.

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.

Constant voltage 'Iron'tophoresis.

The objective of this study was to investigate the feasibility of rapid administration of iron via transdermal route as an alternative to parenteral route of administration. In vitro drug delivery studies were carried out using porcine epidermis mounted on Franz diffusion cells. The effect of chemical permeation enhancers and physical techniques (constant voltage iontophoresis, electroporation and combination of electroporation with iontophoresis) on the transport of ferric pyrophosphate (FPP) was studied. Transepidermal water loss (TEWL) and electrical resistance were measured in order to see the effect of these techniques on the skin barrier function. The amount of FPP permeated was not enhanced significantly with the use of any of the enhancers (P > 0.05). It was found that constant voltage iontophoresis (0.5, 2 or 4 V) for about 30 min across electroporated epidermis (120 V, 100 pulses, 10 ms at 5 Hz) enhanced the delivery of FPP over control in the range of 2- to 42-fold. Hence, a therapeutically required dose of iron could be delivered by transdermal route using electrically-mediated techniques.

A platform for predicting and enhancing model drug delivery across the human nail plate.

PURPOSE: The objective of the present study was to assess the effect of pretreatment using chemical etchants on the delivery of terbinafine hydrochloride (TH) and 5-fluorouracil (5-FU) into and across the human nail plate. METHODS: The TranScreen-N method was used to screen five potential etchants. Based on these results, the dorsal surface of nails was pretreated with chemical etchants, 1% or 10% (w/w) phosphoric acid (PA) or 10% (w/w) lactic acid (LA) gels, for a period of 60 seconds. The nail pretreated with a plain gel formulation (no PA or LA incorporated) was used as the control. RESULTS: Despite the differences in physicochemical properties between TH (log P = 3.3) and 5-FU (log P = -0.83), the in vitro permeation as well as drug load of these drugs in the nail plate was enhanced because of pretreatment with the PA gels, whereas LA pretreatment failed to enhance the drug load and permeation. Optical microscopic and atomic force microscopy studies revealed that the PA enhanced the trans-ungual drug delivery by decreasing the keratin density of the dorsal layer of the nail plate and by microstructural alterations. CONCLUSIONS: This study demonstrated that pretreatment of the nail plate with PA (1% or 10%, w/w) for a short duration could be a potential method of improving the efficiency of topical monotherapy treatment for nail diseases.

Bilayered nail lacquer of terbinafine hydrochloride for treatment of onychomycosis.

The present study aimed to develop bilayered nail lacquer of terbinafine hydrochloride (TH) for treatment of onychomycosis. The composite nail lacquer formed an underlying drug-loaded hydrophilic layer and overlying hydrophobic vinyl layer. The hydrophilic lacquer made of hydroxylpropyl methylcellulose E-15 contained polyethylene glycol 400 (PEG 400) as a drug permeation enhancer. The vinyl lacquer was composed of poly (4-vinyl phenol) as a water-resistant film former. In vitro permeation studies in Franz diffusion cells indicated that the amount of TH permeated across the human cadaver nail in 6 days was 0.32 +/- 0.14, 1.12 +/- 0.42, and 1.42 +/- 0.53 microg/cm(2) from control (hydrophilic lacquer devoid of PEG 400), monolayer (hydrophilic lacquer alone), and bilayered nail lacquers, respectively. A higher nail drug load was seen in vitro with the bilayered lacquer (0.59 +/- 0.13 microg/mg) as compared to monolayer (0.36 +/- 0.09 microg/mg) and control (0.28 +/- 0.07 microg/mg) lacquers. The drug loss despite multiple washing was significantly low (p < 0.001) for the bilayered lacquer owing to the protective vinyl coating. Clinical studies demonstrated the efficacy of bilayered lacquer to achieve better drug load in the nail plate (1.27 +/- 0.184 microg/mg) compared to monolayer (0.67 +/- 0.18 microg/mg) and control (0.21 +/- 0.04 microg/mg) lacquers.

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.

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.

Irontophoresis: transdermal delivery of iron by iontophoresis.

Transdermal delivery of iron can overcome the GI side effects and the discomfort associated with parenteral administration. Slow and prolonged transdermal delivery of iron would also avoid potential oversaturation of transferrin and overcome accumulation of free iron in the systemic circulation. Ferric pyrophosphate (FPP) has been demonstrated to be safe for systemic administration. Passive transdermal delivery of FPP is poor due to the impermeable skin barrier. Irontophoresis was developed for transdermal delivery of FPP. The predictability and programmability of the technique was assessed in vitro across the hairless rat skin. Following Irontophoresis for 6 h in hairless rats, the total serum iron concentration increased from 182.36 +/- 39.93 microg/dL to 317.56 +/- 28.33 microg/dL and the transferrin saturation increased from 44.6% +/- 2.2% to 60.8% +/- 6.7%. Irontophoresis based iron therapy could be relatively more patient compliant, safe and effective treatment for iron deficiency anemia condition.

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.

Transcorneal iontophoresis for delivery of ciprofloxacin hydrochloride.

PURPOSE: To investigate the feasibility of utilizing iontophoresis for delivery of ciprofloxacin hydrochloride to the anterior chamber of the eye and to carry out systematic studies to investigate the effect of electrical protocol on the transcorneal drug delivery. MATERIALS AND METHODS: Effect of current density (0.75 mA/cm(2) to 6.25 mA/cm(2) applied for 5 minutes) on drug permeation across the cornea and drug load in the cornea were investigated in vitro as well as ex vivo studies in porcine cornea model. Tolerability studies were carried out in rabbits. Cytotoxicity studies were conducted in cultured corneal tissue. RESULTS: The drug loaded in the cornea increased with increasing current density. After 5 minutes of iontophoresis, the drug concentration in the receiver compartment fluid (in vitro) or in aqueous humor (ex vivo) was not significantly higher than control (in which electric current was not applied). However, waiting for 6-12 hours after iontophoresis for 5 minutes, the concentrations of drug in aqueous humor in ex vivo studies were approximately 6 and approximately 5-fold higher than control (130.12 +/- 78.99 ng/ml), respectively. Cytotoxicity studies demonstrated the safety of the technique. The application of 6.25 mA/cm(2) for 5 minutes (right eye) did not show any sign of loss of vision and abnormal discharge, redness of eye, or edema when compared to the control left eye. CONCLUSIONS: Transcorneal iontophoresis is a potential method of delivering effective levels of ciprofloxacin hydrochloride into aqueous humor for the treatment of intraocular infections. This study unveils the ability of iontophoresis to rapidly drive ciprofloxacin into the cornea where a drug reservoir is formed, which eventually releases slowly into aqueous humor, eliciting sustained therapeutic effect.