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.

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.

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.

Development of pH- and time-dependent oral microparticles to optimize budesonide delivery to ileum and colon.

A microparticulate system consisting of non-enzymatically degrading poly(dl-lactide-co-glycolide) (PLGA) core and delivering budesonide site specifically to distal ileum and colon was developed. Budesonide-loaded microparticles were fabricated using solvent evaporation technique and formulation variables studied included different molecular weight grades of PLGA polymer as well as concentration of polymer, surfactant and drug. Eudragit S-100, an enteric polymer, was then used to form a coating on the surface of budesonide-loaded PLGA microparticles for site specific delivery to the distal ileum and colon. Budesonide-loaded PLGA microparticles prepared from various formulation parameters showed mean encapsulation efficiencies ranging between 50% and 85% and mean particle size ranging between 10 and 35mum. In vitro release kinetics studies showed a biphasic release pattern with an initial higher release followed by a slower drug release. Increasing polymer and surfactant concentrations exhibited sharply contrasting drug release profiles, with increasing polymer concentrations resulting in a lower drug release and vice versa. The budesonide-loaded PLGA microparticles coated with Eudragit S-100 coating showed a decrease in entrapment efficiency with an accelerated in vitro drug release. Moreover, complete retardation of drug release in an acidic pH, and, once the coating layer of enteric polymer was dissolved at higher pH (7.4 and 6.8), a controlled release of the drug from the microparticles were observed. From the results of this investigation, the application of double microencapsulation technique employing PLGA matrix and Eudragit S-100 coating shows promise for site specific and controlled delivery of budesonide in Crohn's disease.