Effect of alkalizing agent on abuse deterrent potential of multiple-unit ingestion of bilayer abuse-deterrent extended-release tablets using propranolol as model drug for opioids overdose crisis.

The objective of present study is to develop bilayer abuse-deterrent extended-release tablets (ADERTs) using propranolol HCl as model drug for opioids overdose crisis. Bilayer ADERTs were fabricated by direct compression and formulated with polymer matrix in extended-release drug layer coupled with alkalizing and aversive agents in fast-disintegrating pH modifying layer. Various alkalizing agents, like magnesium hydroxide, aluminum hydroxide, calcium carbonate, and calcium hydroxide, were evaluated for their abuse-deterrent potential via in-vitro drug release and extraction studies. Based on the outcomes, magnesium hydroxide was selected as an alkalizing agent, since it raised the pH of dissolving media near to pKa of the drug studied in this investigation. The formulated bilayer ADERTs with magnesium hydroxide provided similar drug release profiles as compared to conventional extended-release tablets for single-unit ingestion. However, upon ingestion of multiple-unit bilayer ADERTs, the fast-disintegrating pH modifying layer increases pH of dissolving media, while extended-release layer increases micro-environmental pH within tablets. Retarding drug release owing to low solubility of basic drug at higher pH was observed. Therefore, the application of alkalizing agent has impact on pH-dependent solubility of drug like opioids and demonstrate its useful potential to be incorporated in bilayer ADERTs for opioids overdose crisis.

Sublingual insulin administration: application of hydroxypropyl beta-cyclodextrin and poloxamer188 as permeation enhancers.

The objective of this investigation is to investigate the feasibility of sublingual insulin administration. Insulin solutions formulated with permeation enhancers (HPßCD/poloxamer 188) and their in-vitro and in-vivo performances were evaluated. Thereafter, insulin fast-dissolving film was further developed to have similar properties, upon dissolving the film, of the optimized insulin solution. In-vitro performance was evaluated via effect of HPßCD and/or poloxamer 188 concentration across cellulose acetate membrane and porcine esophagus. In-vivo performance was evaluated via pharmacodynamic and pharmacokinetic profiles of insulin solution administered. Cumulative amounts of insulin permeated at 60 min formulated with HPßCD (5%), poloxamer 188 (0.5%), and their combination were 1.31, 3.23, and 4.99 IU/cm2, respectively, indicating an additive effect of combination of HPßCD and poloxamer 188. Insulin-induced hypoglycemic effect was observed for insulin solutions with combination of HPßCD and poloxamer 188 after sublingual administration to Sprague-Dawley rats. Microscopic evaluation of porcine oesophageal tissue indicates that HPßCD and poloxamer 188 are safe. Furthermore, the cumulative amount permeated across cellulose acetate membrane at 30 min was 1.13 and 1.00 IU/cm2 for insulin solution and fast-dissolving film, respectively, demonstrating to be similar. In conclusion, the use of HPßCD/poloxamer 188 is feasible for the development of sublingual insulin solutions/films.

Effect of ionization of drug on drug solubilization in SMEDDS prepared using Capmul MCM and caprylic acid.

The purpose of this study was to investigate the effect of ionization of drug on drug solubilization in SMEDDS (self-microemulsifying drug delivery system) prepared using Capmul MCM and caprylic acid. Solubilization capacity of blank SMEDDS dispersions for danazol, indomethacin and haloperidol as model drugs was determined. Based on the outcomes of solubilization capacity study, drug-loaded SMEDDS formulations were prepared and subjected to dispersion/precipitation study and droplet size analysis. Blank SMEDDS dispersions exhibited the highest solubilization capacity for haloperidol followed by indomethacin and danazol. Furthermore, the solubilization of the three drugs in blank SMEDDS dispersions was explained by a modified mathematical model. Dispersion/precipitation studies indicate that drug-loaded SMEDDS formulations exhibited superiority in solubilizing the drugs in comparison to their respective drug powder. In addition, indomethacin and haloperidol were found to reduce the droplet size of the microemulsions while danazol did not affect droplet size formation for drug-loaded SMEDDS formulations. These findings suggest that ionization of drug affects drug solubilization, droplet size formation, drug loading and drug dispersion/precipitation profiles for the SMEDDS formulations.

Transdermal iontophoretic delivery of tacrine hydrochloride: Correlation between in vitro permeation and in vivo performance in rats.

The aim of present investigation is to evaluate the feasibility of transdermal iontophoretic delivery of tacrine hydrochloride in Sprague Dawley (SD) rats using anodal iontophoretic patches and to correlate plasma tacrine concentration profiles to in vitro tacrine permeation flux. In vitro skin permeation studies were carried out across artificial membrane CELGRAD® 2400, freshly excised SD rat abdominal skin, freshly excised hairless rat abdominal skin, and frozen pig skin to examine the role of permeation membranes. Furthermore, plasma profiles with an application of 0.1-0.3mA current strength and tacrine concentration loading of 5-20mg/ml were obtained in SD rats. The tacrine plasma profiles were fitted to one-compartmental model using WinNonlin and in vivo transdermal absorption rates were then correlated to in vitro permeation profiles using various approaches. Tacrine permeation across membranes revealed current dependent interspecies differences at lower current strength application which diminished at higher current strength application, whereas, no significant difference in tacrine permeation was observed across fresh and frozen SD rat skin under 0.2mA current application. In vivo studies confirmed current and concentration dependent tacrine plasma profiles with possible tacrine depot formation under the skin in-line with earlier in vitro results. Correlation of in vivo transdermal absorption rates to in vitro permeation profiles revealed higher in vitro permeation fluxes compare to in vivo transdermal absorption rates at varied combination of current strength and concentrations. Present in vivo studies support the earlier published in vitro findings and tacrine plasma profiles show a potential to reach therapeutic effective concentration of tacrine hydrochloride to provide a platform for pre-programmed tacrine delivery.

Application of design of experiments for formulation development and mechanistic evaluation of iontophoretic tacrine hydrochloride delivery.

OBJECTIVE: The objective of this investigation is to develop mathematical equation to understand the impact of variables and establish statistical control over transdermal iontophoretic delivery of tacrine hydrochloride. In addition, possibility of using conductivity measurements as a tool of predicting ionic mobility of the participating ions for the application of iontophoretic delivery was explored. METHODS: Central composite design was applied to study effect of independent variables like current strength, buffer molarity, and drug concentration on iontophoretic tacrine permeation flux. Molar conductivity was determined to evaluate electro-migration of tacrine ions with application of Kohlrausch's law. RESULTS: The developed mathematic equation not only reveals drug concentration as the most significant variable regulating tacrine permeation, followed by current strength and buffer molarity, but also is capable to optimize tacrine permeation with respective combination of independent variables to achieve desired therapeutic plasma concentration of tacrine in treatment of Alzheimer's disease. Moreover, relative higher mobility of sodium and chloride ions was observed as compared to estimated tacrine ion mobility. CONCLUSIONS: This investigation utilizes the design of experiment approach and extends the primary understanding of imapct of electronic and formulation variables on the tacrine permeation for the formulation development of iontophoretic tacrine delivery.

Formulation and rheological evaluation of ethosome-loaded carbopol hydrogel for transdermal application.

OBJECTIVE: To select a suitable ethosome-loaded Carbopol hydrogel formulation, specifically tailored for transdermal application that exhibits (i) plastic flow with yield stress of approximately 50-80 Pa at low polymer concentration, (ii) relatively frequency independent elastic (G') and viscous (G″) properties and (iii) thermal stability. METHODS: Carbopol (C71, C934, C941, C971 or C974) hydrogels were prepared by dispersing Carbopol in distilled water followed neutralization by sodium hydroxide. The effects of Carbopol grade, Carbopol concentration, ethosome addition and temperature on flow (yield stress and viscosity) and viscoelastic (G' and G″) properties of Carbopol hydrogel were evaluated. Based on the aforementioned rheological properties evaluated, suitable ethosome-loaded Carbopol hydrogel was selected. In-vitro permeation studies of diclofenac using rat skin were further conducted on ethosome-loaded Carbopol hydrogel along with diclofenac-loaded ethosomal formulation as control. RESULTS: Based on preliminary screening, C934, C971 and C974 grades were selected and further evaluated for flow and viscoelastic properties. It was observed that ethosome-loaded C974 hydrogel at concentration of 0.50 and 0.75% w/w, respectively, demonstrated acceptable plastic flow with distinct yield stress and a frequency independent G' and G″. Furthermore, the flow and viscoelastic properties were maintained at the 4, 25 and 32 °C. The results from in vitro skin permeation studies indicate that ethosome-loaded C974 hydrogel at 0.5% w/w polymer concentration exhibited similar skin permeation as that of ethosomal formulation. CONCLUSION: The results indicate that suitable rheological properties of C974 could facilitate in achieving desired skin permeation of diclofenac while acting as an efficient carrier system for ethosomal vesicles.

Elucidation of intestinal absorption mechanism of carvedilol-loaded solid lipid nanoparticles using Caco-2 cell line as an in-vitro model.

Enhanced oral bioavailability of poorly aqueous soluble drugs encapsulated in solid lipid nanoparticles (SLNs) via lymphatic delivery has been documented. Since no in-vitro lymphoid tissue is currently available, human excised Caco-2 cell monolayer could be alternative tissue for development of an in-vitro model to be used as a screening tool before animal studies are undertaken. Therefore, optimized carvedilol-loaded SLNs (FOPT-SLNs) were prepared, characterized, and evaluated using Caco-2 cell line as an in-vitro model. Physical mixture of components of FOPT-SLNs (FOPT-PM) and carvedilol solution were used as control groups. From the studies of effect of SLNs concentration and cells incubation time, suitable carvedilol concentration and incubation time were selected for the model in which cells were subjected to five pretreatments for 24 h or 1 h of cell incubation and then followed with treatment of FOPT-SLNs, FOPT-PM or 100 µg/mL solution of carvedilol, for additional 24 h of cell incubation. The results obtained in this model suggest that main absorption mechanism of FOPT-SLNs could be endocytosis and, more specifically, clathrin-mediated endocytosis. When Transwell® permeable supports were used for the cells, carrier-mediated mechanism for FOPT-SLNs and passive absorption mechanism (transcellular and paracellular) for FOPT-PM and drug solution were concluded.

Application of Capmul MCM and caprylic acid for the development of danazol-loaded SEDDS.

The feasibility of using Capmul MCM and caprylic acid (medium-chain triglyceride pre-digestion products) as the lipid phase was investigated for the development of self-emulsifying drug delivery system (SEDDS) as a carrier system to enhance solubilization of poorly water-soluble danazol. The composition of SEDDS was first evaluated by phase diagrams of lipid/surfactant/water systems. Thereafter, danazol-loaded SEDDS was formulated and subjected to dispersion/precipitation study in distilled water, HCl buffer, phosphate buffer, or biorelevant aqueous media. The mechanism of danazol dispersion was investigated by comparing the solubilization capacity of blank SEDDS dispersed in various aqueous media with respective dispersion/precipitation profiles obtained. Phase diagrams showed that at least 30% (w/w) Cremophor RH40, as the surfactant, was needed to properly emulsify Capmul MCM:caprylic acid (1:1), as the lipid phase. Different extent of danazol precipitation was observed upon the dispersion of danazol-loaded SEDDS in different aqueous media. Danazol precipitation was dominated by the solubilization capacity of danazol, which was influenced by the ratio of Capmul MCM:CA and Cremophor RH40, pH of aqueous media, gastrointestinal composition, and blank SEDDS concentration.

Solubility and dissolution enhancement strategies: current understanding and recent trends.

Identification of lead compounds with higher molecular weight and lower aqueous solubility has become increasingly prevalent with the advent of high throughput screening. Poor aqueous solubility of these lipophilic compounds can drastically affect the dissolution rate and subsequently the drug absorbed in the systemic circulation, imposing a significant burden of time and money during drug development process. Various pre-formulation and formulation strategies have been applied in the past that can improve the aqueous solubility of lipophilic compounds by manipulating either the crystal lattice properties or the activity coefficient of a solute in solution or both, if possible. However, despite various strategies available in the armor of formulation scientist, solubility issue still remains an overriding problem in the drug development process. It is perhaps due to the insufficient conceptual understanding of solubility and dissolution phenomenon that hinders the judgment in selecting suitable strategy for improving aqueous solubility and/or dissolution rate. This article, therefore, focuses on (i) revisiting the theoretical and mathematical concepts associated with solubility and dissolution, (ii) their application in making rationale decision for selecting suitable pre-formulation and formulation strategies and (iii) the relevant research performed in this field in past decade.

Quality by design approach for formulation, evaluation and statistical optimization of diclofenac-loaded ethosomes via transdermal route.

The objective of this study was to fabricate and understand ethosomal formulations of diclofenac (DF) for enhanced anti-inflammatory activity using quality by design approach. DF-loaded ethosomal formulations were prepared using 4 × 5 full-factorial design with phosphatidylcholine:cholesterol (PC:CH) ratios ranging between 50:50 and 90:10, and ethanol concentration ranging between 0% and 30% as formulation variables. These formulations were characterized in terms of physicochemical properties and skin permeation kinetics. The interaction of formulation variables had a significant effect on both physicochemical properties and permeation kinetics. The results of multivariate regression analysis illustrated that vesicle size and elasticity of ethosomes were the dominating physicochemical properties affecting skin permeation, and could be suitably controlled by manipulation of formulation variables to optimize the formulation and enhance the skin permeation of DF-loaded ethosomes. The optimized formulation had ethanol concentration of 22.9% and PC:CH ratio of 88.4:11.6, with vesicle size of 144 ± 5 nm, zeta potential of -23.0 ± 3.76 mV, elasticity of 2.48 ± 0.75 and entrapment efficiency of 71 ± 4%. Permeation flux for the optimized formulation was 12.9 ± 1.0 µg/h cm(2), which was significantly higher than the drug-loaded conventional liposome, ethanolic or aqueous solution. The in vivo study indicated that optimized ethosomal hydrogel exhibited enhanced anti-inflammatory activity compared with liposomal and plain drug hydrogel formulations.

Influence of electronic and formulation variables on transdermal iontophoresis of tacrine hydrochloride.

Freshly excised rat skin and side-by-side permeation cells were used to study the effect of electronic and formulation variables on transdermal iontophoretic delivery of tacrine. Current strength at 0.1-0.3 mA was observed to be the driving force resulting in tacrine permation flux of 30.3-366.6 µg/cm(2)/h. Depot formation of tacrine and altered skin permeability resulted in post iontophoretic flux even after termination of applied current. Increase in the duration of current application did not show significant difference in tacrine permeation flux upto 6 h. Tacrine permeation was directly proportional to tacrine concentration upto 10 mg/ml but further increase in concentration (upto 20 mg/ml) exhibited permeation flux plateau. Buffer molarity had an inverse relationship on permeation flux and the presence of co-ions in formulation exhibited reduced permeation flux. Permeation flux decreased when pH of formulation was successively increased from 7.0 to 10.0 suggesting electromigration of tacrine. Alternate buffer systems including HEPES and Tris showed improved tacrine permeation due to their larger ion size compared to phosphate buffer ions. The results of this study show that transdermal tacrine permeation can be controlled by electronic and formulation variables which would be useful for the development of transdermal iontophoretic delivery of tacrine for the treatment of Alzehimer's disease.

Preparation, in vitro evaluation and statistical optimization of carvedilol-loaded solid lipid nanoparticles for lymphatic absorption via oral administration.

Carvedilol-loaded solid lipid nanoparticles (SLNs) were prepared using solubility parameter (δ) to select the lipid, and hot homogenization to fabricate SLNs. The effect of concentration of Compritol 888 ATO (COMP) and Poloxamer 188 (P-188) on the particle size of blank SLNs was studied using the design of experiments. Further narrow concentration range of COMP and P-188 was selected and carvedilol-loaded SLNs were prepared to obtain an optimized formulation which was lyophilized (L-SLNs), transformed into enteric compression-coated tablet and evaluated for drug release, X-ray diffraction and cellular uptake mechanism. COMP was chosen as lipid due to its least value of Δδ with carvedilol. The optimized formulation (7.5% COMP, 5.0% P-188 and 1.11% carvedilol) had 161 nm particle size and 94.8% entrapment efficiency. The enteric-coated carvedilol-loaded SLNs tablet protected carvedilol from acidic environment and similar prolonged release profiles were obtained from L-SLNs, core tablet and enteric-coated tablet. Absence of crystalline carvedilol XRD peak indicated the presence of amorphous carvedilol in SLNs. Higher carvedilol uptake from SLNs compared to drug solution in the Caco-2 cell line exhibited a potential prolonged drug release. Moreover, upon cellular uptake, SLNs could then enter the lymphatic system which will avoid first pass metabolism and hence higher oral bioavailability.

Transdermal delivery of diclofenac using water-in-oil microemulsion: formulation and mechanistic approach of drug skin permeation.

The objective of the present investigation was to enhance skin permeation of diclofenac using water-in-oil microemulsion and to elucidate its skin permeation mechanism. The w/o microemulsion formulations were selected based on constructed pseudoternary phase diagrams depending on water solubilization capacity and thermodynamic stability. These formulations were also subjected to physical characterization based on droplet size, viscosity, pH and conductivity. Permeation of diclofenac across rat skin using side-by-side permeation cells from selected w/o microemulsion formulations were evaluated and compared with control formulations. The selected w/o microemulsion formulations were thermodynamically stable, and incorporation of diclofenac sodium into microemulsion did not affect the phase behavior of system. All microemulsion formulations had very low viscosity (11-17 cps) and droplet size range of 30-160 nm. Microemulsion formulations exhibited statistically significant increase in diclofenac permeation compared to oily solution, aqueous solution and oil-Smix solution. Higher skin permeation of diclofenac was observed with low Smix concentration and smaller droplet size. Increase in diclofenac loading in aqueous phase decreased the partition of diclofenac. Diclofenac from the oil phase of microemulsion could directly partition into skin, while diclofenac from the aqueous droplets was carried through skin by carrier effect.

Formulation and evaluation of time-controlled triple-concentric mefenamic acid tablets for rheumatoid arthritis.

A triple-concentric time-controlled release mefenamic acid (MA) tablet was developed using Carbopol and Ethocel polymers. The burst dose was programed to release immediately after an ingestion of tablet to be followed by a lag period of 2-4 h, and thereafter an 8 h controlled release of MA from core tablet. Core tablets were prepared using Carbopols 971P, 974P, 71G or 907 at various concentrations. The core tablet provided a controlled release of MA and the release rate decreased with increasing polymer concentration. Highly cross-linked Carbopol 974P released MA at a faster rate compared to release from Carbopol 971P with medium degree of cross-linking. Carbopols 71G and 971P exhibited essentially similar release rates. Carbopol 907, a linear polymer, showed fastest release of MA. The extent of uptake of dissolution medium by core tablets was inversely related to the rate of release of MA from the tablets. Compression coating of core tablet with Ethocel provided the lag period to delay release of MA from core tablet. Increase in lateral coating thickness decreased MA release and increased lag period. Compression forces applied during compression coating with Ethocel for lag period, and immediate-release MA coating for burst release did not affect the integrity of core tablet.

Statistical optimization of insulin-loaded Pluronic F-127 gels for buccal delivery of basal insulin.

The principle of statistical optimization was employed to fabricate insulin-loaded Pluronic F-127 (PF-127) gel formulations having the potential for buccal delivery of basal insulin. A two-level resolution III fractional factorial design was applied to simultaneously evaluate five independent formulation variables: PF-127 concentration, insulin concentration, sodium sulfate concentration, hydroxypropylmethyl cellulose (HPMC) concentration, and presence of sodium glycocholate. The amount of insulin released and permeated from gels as well as gelation time and mucoadhesion force of gels were measured and used as dependent response variables for formulation optimization. Optimization of a gel formulation was achieved by applying constrained optimization via regression analysis. In vitro permeation flux of insulin from the optimized formulation through procine buccal mucosa was 93.17 (±0.058, n = 3) µg/cm(2). Plasma insulin levels following buccal administration of the optimized formulation at 10, 25 and 50 IU/kg to healthy rats were found to be dose dependent and basal insulin levels were maintained at least for 8 h. Furthermore, continuous hypoglycemia for at least 8 h was observed with 89%, 51% and 25% of blood glucose reduction, respectively, for these three doses. The results of this investigation conclude the feasibility of development of optimized buccal insulin-loaded Pluronic F-127 gels for basal insulin delivery.

Development and evaluation of controlled release ibuprofen matrix tablets by direct compression technique.

This investigation reports the development and evaluation of controlled release ibuprofen matrix tablets. Matrix tablets weighing 400 mg were fabricated by directly compressing ibuprofen (100 mg) with Eudragit RSPO and Avicel PH 101. The release of ibuprofen was dependant on concentration of Eudragit in the formulation. Varying Eudragit concentration from 10-50% of the formulation (in increments of 5%) revealed that in 4 h, tablets containing 50% Eudragit released about 40% ibuprofen compared to 100% released from tablets containing 10% Eudragit. Following analysis of release mechanism using various models available in literature, release of ibuprofen from matrix tablets was dominated by polymer diffusion-controlled mechanism at least for first 4 h. Thereafter, the release mechanism became more complicated and lost controlled release by diffusion due to change of tablet integrity, such as erosion of polymer matrix. In conclusion, controlled release ibuprofen matrix tablets with desired drug release rate can be fabricated by various formulation variables with direct compression technique.

Development and in vitro evaluation of insulin-loaded buccal Pluronic F-127 gels.

Insulin-loaded buccal Pluronic F-127 (PF-127) gel formulations were fabricated to study the effect of PF-127 concentration, insulin concentration, presence of salt, addition of polymer, and permeation enhancer on their gelation time, mucoadhesion force, release and permeation characteristics of insulin from the gels. Thereafter, the principle of statistical optimization to prepare a gel formulation having the potential for buccal delivery of basal insulin in diabetic patients was employed. The gelation time decreased as the concentration of PF-127 increased. Presence of salts as well as addition of polymer, such as methyl cellulose (MC) and hydroxypropylmethyl cellulose (HPMC) decreased the gelation time. An increase in PF-127 concentration and addition of MC and HPMC increased the mucoadhesion force of the gel formulations. Release and permeation of insulin from the gel formulations decreased with increased concentration of PF-127, presence of salts, and addition of MC and HPMC. Permeation of insulin from the optimized gel formulation was 93.17 (+/- 0.058, n = 3) microg/cm(2) which was not only found in close agreement with predicted results from the model equations used for the formulation optimization but also considered comparable to clinical setting. Therefore, the development of optimized buccal insulin-loaded Pluronic F-127 gels using a statistical experimental design is feasible.

Application of hydrogel polymers for development of thyrotropin releasing hormone-loaded adhesive buccal patches.

To utilize hydrogels for fabricating thyrotropin releasing hormone (TRH) adhesive buccal patches, type of hydrogels such as polyacrylic acids (Polycarbophil AA1, Carbopols 934P, 974P and 971P), celluloses (HPMC K4M, K4MCR and K15M), polysaccharide (sodium alginate) and polyacrylic acid combinations with either cellulose or polysaccharide were evaluated for adhesion force, water uptake and swelling capacity. Upon the characterization of hydrogel polymers, TRH-loading of patches fabricated from these hydrogels was evaluated at various polymer concentrations, combinations and ratios and then in vitro release kinetics of TRH from these patches were studied. Results indicated that maximum adhesion force was shown by polyacrylic acids. Adhesive force of polymer combination mainly resulted from combination of adhesive force, according to ratio proportion used, of each polymer without any superimposed effect of polymer combination. Polycarbophil AA1 showed highest water uptake and swelling capacity. Maximum TRH-loading was obtained with sodium alginate and Polycarbophil AA1 and sodium alginate combination. TRH release profiles revealed that release was sustained from Polycarbophil AA1 and its combination with celluloses or polysaccharide at 2:1 level of polymer ratio. Based on adhesion, loading and release characteristics, patches of Polycarbophil AA1 with K4M, K4MCR and sodium alginate were concluded to be suitable for further development.

Transdermal iontophoresis of hydromorphone across hairless rat skin in vitro.

The feasibility of delivering hydromorphone by transdermal iontophoresis to obtain therapeutically effective analgesic concentrations for the management of cancer-related pain was evaluated. Anodal iontophoresis was performed, and the effect of current strength, current duration, solution pH, presence of buffer ions, and drug concentration on the transdermal permeation of hydromorphone was investigated in vitro. Freshly excised full-thickness hairless rat skin and side-by-side permeation cells connected to the Phoresor II with Ag/AgCl electrodes was used. The flux of hydromorphone was observed to significantly increase (P < 0.05) from 72.04-280.30 microg/cm(2)/h with increase in current strength from 0.10-0.50 mA. A linear relationship was obtained between hydromorphone flux and current strength. Furthermore, the flux of hydromorphone was influenced by solution pH and presence of buffer ions. Also, the in vitro permeation flux of hydromorphone was observed to significantly increase (P < 0.05) with a 10-fold increase in hydromorphone hydrochloride concentration from 0.01-0.10 M. However, with further increase to 0.50 M, there was no significant difference in flux. These results show that by manipulating electronic and formulation variables, the transdermal iontophoretic delivery of hydromorphone can be controlled, and therapeutically effective concentrations of hydromorphone for the management of cancer-related pain can be obtained.

Transdermal iontophoresis: impact on skin integrity as evaluated by various methods.

Transdermal iontophoresis, a noninvasive technique that facilitates drug transport through the skin by the use of an external electrical field, has expanded the scope of drugs that can be delivered transdermally and enables programmable drug delivery. In general, transdermal iontophoresis is considered to be a safe procedure, associated with moderate erythema and tingling sensations. However, ensuring that the skin barrier maintains its integrity during iontophoresis is an essential factor to increase its clinical applicability. This review focuses on the effect of transdermal iontophoresis on the integrity of skin, as evaluated by impedance spectroscopy, microscopy, differential scanning calorimetry, infrared spectroscopy, X-ray diffraction, transepidermal water loss, laser doppler velocimetry, visual scoring, chromameter readings, and patient evaluation studies.