Development of matrix patches for transdermal delivery of a highly lipophilic antiestrogen

The aim of this study was to develop matrix-type transdermal systems (TDSs) containing the highly lipophilic (log P = 5.82) antiestrogen (AE) and the permeation enhancers propylene glycol and lauric acid. For that purpose, permeation of AE from various adhesive matrices through excised skin of hairless mice was evaluated. It was found that pretreatment of the skin with permeation enhancers raised the transdermal flux of subsequently applied antiestrogen. Highest steady-state transdermal fluxes (1.1 µg cm^-2 h^-1) were obtained from Gelva®, polyacrylate adhesive, followed by 0.55 µg cm^-2 h^-1 from Oppanol® polyisobutylene, 0.31 µg cm^-2 h^-1 from BIO-PSA® silicone, and 0.12 µg cm^-2 h^-1 from Sekisui polyacrylate matrices. In order to develop TDS with high content of fluid permeation enhancer propylene glycol, two different strategies were investigated. One strategy was the addition of hydroxypropyl cellulose (HPC) as thickening agent to Gelva matrices. This allowed for propylene glycol loading levels of up to 30%, resulting in transdermal AE fluxes of 0.09 µg cm^-2 h^-1. On the other hand, a fleece-laminated backing foil was loaded with the described permeation enhancer formulation and laminated with polyacrylate adhesive layer, resulting in transdermal AE fluxes of 0.06 µg cm^-2 h^-1. However, application of these TDSs on skin pretreated with permeation enhancers raised the fluxes to 2.6 µg cm^-2 h^-1 from Gelva/HPC and 0.46 µg cm^-2 h^-1 from fleece/Sekisui.     

Investigation of nanostructured lipid carriers for transdermal delivery of flurbiprofen

The aim of this study was to develop nanostructured lipid carriers (NLC) for transdermal delivery of Flurbiprofen (FP). The physical stability of FP-NLC and its in vitro permeation profile were investigated. After three months of storage at 4°C, 20°C, and 40°C, no significant differences between the evaluated parameters, such as pH value, the entrapment efficiency, particle size, and zeta potential were observed. In in vitro permeation studies, the cumulative permeated amounts and the release rate from FP-NLC were 412.53 ± 21.37 μg/cm² and 35.25 μg/cm²/h after 12 h (n = 6), respectively, while from saturated FP-PBS (pH = 7.4) were 90.83 ± 8.67 μg/cm² and 6.99 μg/cm²/h, respectively. These results indicated that the FP-NLC were with good physical stability and were able to improve the permeated amounts and the release rate of FP. It could potentially be exploited as a carrier with improved drug entrapment efficiency and permeated amount in the transdermal delivery of FP.     

Transdermal delivery of ketorolac tromethamine: effects of vehicles and penetration enhancers

The effects of vehicles and penetration enhancers on the in vitro permeation of ketorolac tromethamine (KT) across excised hairless mouse skins were investigated. Among pure vehicles examined, propylene glycol monolaurate (PGML) showed the highest permeation flux, which was 94.3 ± 17.3 µg/cm²/h. Even though propylene glycol monocaprylate (PGMC) alone did not show high permeation rate, the skin permeability of KT was markedly increased by the addition of diethylene glycol monoethyl ether (DGME); the enhancement factors were 19.0 and 17.1 at 20% and 40% of DGME, respectively. When DGME was added to PGML, the permeation fluxes were almost two times at 20-60% of DGME compared to PGML alone. In the cosolvent system consisting of propylene glycol (PG)-oleyl alcohol, the permeation rate increased as the ratio of PG increased. In the study to investigate the effect of drug concentration on the permeation rate of KT, the permeation rates increased as the drug concentration increased in all vehicles used, and the dramatic increase in permeation rate was obtained when the drug concentration was higher than its solubility. For the effects of fatty acids on the permeation of KT, five fatty acids were added to PG at concentrations of 1%-, 3%-, 5%- and 10%-caprylic acid, capric acid, lauric acid, oleic acid, and linoleic acid. The enhancing effects of fatty acids were different, depending on the concentration as well as the sort of fatty acids. The highest enhancing effect was attained with 10% caprylic acid in PG; the permeation flux was 113.6 ± 17.5 µg/cm²/h. The lag time of KT was reduced as the concentration of fatty acids increased except for caprylic acid.     

Effect of nerodilol and carvone on in vitro permeation of nicorandil across rat epidermal membrane

The objective of the study was to investigate the effect of nerodilol and carvone on the in vitro transdermal delivery of nicorandil so as to fabricate a membrane-moderated transdermal therapeutic system. The in vitro permeation studies were carried across the rat epidermal membrane from the hydroxypropyl methylcellulose (HPMC) gels (prepared with 70:30 v/v ethanol-water) containing selected concentrations of a terpene such as nerodilol (0% w/w, 4% w/w, 8% w/w, 10% w/w, or 12% w/w) or carvone (0% w/w, 4% w/w, 8% w/w, 12% w/w, or 16% w/w). The amount of nicorandil permeated (Q₂₄) from HPMC gel drug reservoir without a terpene was 3424.6 ± 51.4 μg/cm², and the corresponding flux of the drug was 145.5 ± 2.2 μg/cm²· h. The flux of nicorandil increased with an increase in terpene concentration in HPMC gel. It was increased ranging from 254.9 ± 3.1 to 375.7 ± 3.2 μg/cm²·h or 207.6 ± 4.7 to 356.7 ± 15.3 μg/cm²· h from HPMC gels containing nerodilol (4% w/w to 12% w/w) or carvone (4% w/w to 16% w/w), respectively. Nerodilol increased the flux of nicorandil by about 2.62-folds whereas carvone increased the flux of the drug by about 2.49-folds across the rat epidermal membrane. The results of the Fourier Transform Infrared (FT-IR) study indicated that the enhanced in vitro transdermal delivery of nicorandil might be due to the partial extraction of stratum corneum lipids by nerodilol or carvone. It was concluded that the terpenes, nerodilol and carvone, produced a marked penetration enhancing effect on the transdermal delivery of nicorandil that could be used in the fabrication of membrane-moderated transdermal therapeutic systems.     

Effect of urea and pantothenol on the permeation of progesterone through excised rat skin from polymer matrix systems

Standard in vitro permeation experiments, using excised rat skin, were carried out to establish the release profile and permeation behavior of progesterone from polymethacrylate (PMA), polyvinylpyrrolidon (PVP), and polyvinylalcohol (PVA) transdermal systems. Data obtained show significant differences in release characteristics from each polymer systems. The greatest amount of progesterone was released from the PVA system. The influence of urea and pantothenol on progesterone release was also investigated. Release data were compared with the permeation rates of progesterone across excised rat skin. The highest permeation rates were measured from PVA matrices containing 5% urea (860 ± 138 μg/cm²; cumulative amount permeated in 24 hr) and from PVP matrices containing 6% pantothenol (660 ± 73 μg/cm²; cumulative amount permeated in 24 hr). A good correlation between release and permeation data was found with the polymer matrices; however, this was not the case when additives were included.     

Transdermal delivery of ondansetron hydrochloride: effects of vehicles and penetration enhancers

The effects of vehicles and penetration enhancers on the in vitro permeation of ondansetron hydrochloride (OS) across dorsal hairless mouse skins were investigated. Various types of vehicles, including ester, alcohol, and ether and their mixtures were used, and then a series of fatty acids and fatty alcohols were employed as enhancers. Among pure vehicles used, water and ethanol showed high permeation fluxes, which were 48.2 ± 23.7 and 41.9 ± 17.9 µg/cm² per h, respectively. Even though propylene glycol monocaprylate (PGMC) alone did not show a high permeation rate, the skin permeability of OS was increased by the addition of diethylene glycol monoethyl ether (DGME); the highest flux was achieved at 40% of DGME. Also, the combination of PGMC and ethanol (80:20) or PGMC and propylene glycol (PG) (60:40) increased the permeation flux by six- and two-fold, respectively, compared to PGMC alone. The synergistic enhancement was also obtained by using PG-oleyl alcohol (OAl) cosolvent. The greatest flux was attained by the addition of unsaturated fatty acids at 3% concentration to PG. The enhancement factors with the addition of oleic acid or linoleic acid to PG were about 1250 and 450, respectively. But saturated fatty acids failed to show a significant enhancing effect. When the PGMC-DGME (60:40) cosolvent system was used as a vehicle, all fatty acids, including unsaturated fatty acids, failed to show significant enhancing effects. The results indicate that the combinations of oleic acid, linoleic acid, or oleyl alcohol with PG, or PGMC-DGME (60:40) cosolvent could be used for the design of the OS transdermal system.     

Controlled Transdermal Mucolytic Delivery System: In Vivo Performance

A multicomponent transdermal bromhexine delivering system was developed. The drug permeation across the human cadavar skin from either sexes was determined and found to be dependent on age, sex and site of skin. The system that could control the the delivery of the drug to allow it to permeate across the skin at a rate that is required to achieve the therapeutic concentration was selected and chosen for in vivo performance evaluation. Prior to in human volunteers availability testing the designed system was evaluated in rabbits and the system exhibiting desirable performance was redesigned for evaluation in human volunteers.T.P.S_o system delivering 1.991±0.116 mg bromhexine/cm² hr with a 453 μg/cm² priming dose was tested in human volunteers and found to maintain bromhexine blood level at or around peak plasma level for 20-24 hrs. The study reveals that bromhexine holds potential for transdermal delivery with a need of further clinical and pharmacodynamic studies.     

Transdermal and buccal delivery of methylxanthines through human tissue in vitro

We examined the in vitro permeation of central nervous stimulants—caffeine, theophylline, and theobromine across human skin with the aid of six chemical enhancers. It was found that oleic acid was the most potent enhancer for all three methylxanthines. Further optimization studies with different solvents showed that caffeine transport could be enhanced to give flux values up to 585 μg/cm².hr^-1. Theobromine and theophylline delivery rates proved insufficient. An additional study involving a buccal tissue equivalent showed that this membrane was more permeable than skin for all model actives tested and would offer an alternate way of delivery.     

Preparation, evaluation, and NMR characterization of vinpocetine microemulsion for transdermal delivery

A novel microemulsion was prepared to increase the solubility and the in vitro transdermal delivery of poorly water-soluble vinpocetine. The correlation between the transdermal permeation rate and structural characteristics of vinpocetine microemulsion was investigated by pulsed field gradient nuclear magnetic resonance (PFG-NMR). For the microemulsions, oleic acid was chosen as oil phase, PEG-8 glyceryl caprylate/caprate (Labrasol®) as surfactant (S), purified diethylene glycol monoethyl ether (Transcutol P®) as cosurfactant (CoS), and the double-distilled water as water phase. Pseudo-ternary phase diagrams were constructed to obtain the concentration range of each component for the microemulsion formation. The effects of various oils and different weight ratios of surfactant to cosurfactant (S/CoS) on the solubility and permeation rate of vinpocetine were investigated. Self-diffusion coefficients were determined by PFG-NMR in order to investigate the influence of microemulsion composition with the equal drug concentration on their transdermal delivery. Finally, the microemulsion containing 1% vinpocetine was optimized with 4% oleic acid, 20.5% Labrasol, 20.5% Transcutol P, and 55% double-distilled water (w/w), in which drug solubility was about 3160-fold higher compared to that in water and the apparent permeation rate across the excised rat skin was 36.4 ± 2.1 µg/cm²/h. The physicochemical properties of the optimized microemulsion were examined for the pH, viscosity, refractive index, conductivity, and particle size distribution. The microemulsion was stable after storing more than 12 months at 25°C. The irritation study showed that the optimized microemulsion was a nonirritant transdermal delivery system.     

Evaluation of the physicochemical stability and skin permeation of glucosamine sulfate

Glucosamine sulfate (GS) is known to stop the degenerative process of osteoarthritis. Because most of the GS formulation on the market is in the oral form, an alternative formulation such as a transdermal delivery system (TDS) is necessary in order to increase patient compliance. As the initial step to develop a TDS of GS, the physicochemical stability and permeation study in rat skin were examined. Evaluation of the stability of GS at different pHs showed the compound to be most stable at pH 5.0. The degradation rate constant at 25°C was estimated to be 5.93 ×10^- 6 hr^- 1 (t₉₀~ 2.03 years) in a pH 5 buffer solution. Due to its hydrophilic characteristic, low skin permeability was expected of GS. However, the skin permeation rate was determined to be 13.27 µg/cm²/hr at 5% concentration. Results of this study suggest the possibility of developing GS into a transdermal delivery system.     

Physicochemical Characteristics of Commercial Aluminum Hydroxycarbonate Gels

Four commercial samples of AHC each from different manufacturer or distributor in the USA, Canada and Mexico, were studied to determine particle size distribution, viscosity, rate of settling, pH, point of zero charge (PZC), IR spectra and sodium content. These properties are of interest to the raw material manufacturer, the formulator and the consumer, since they impart desirable characteristics to the finished product. It was found in this work, that the average particle size varied between 3.90 and 2.01 μm with standard deviations of 4.10 μm and 3.99 μm, respectively; the viscosities of 4% (w/w) equivalent Al(OH)₃, suspensions, ranged from 49 to 10 mPa.s and the sediment fractions after 24 hours for these suspensions oscillated from 0.44 to 0.59. The pH was between 5.61 and 7.60 and the PZC varied from 6.45 to 7.33. The sodium content found in this work was between 0.0406 and 0.5620 g/L. The infrared spectra obtained for the obtained for the four samples indicated the presence of the absorption bands assigned to carbonates in the range of 1525 and 1518 cm^-1, 1440 cm^-1, 1104 and 1088 cm^-1 and 857 to 843 cm^-1. These results are discussed from the implications that they have to the manufacturer and to the formulator, including the aesthetics of the finished product.     

Development of a Transdermal Delivery Device for Melatonin In Vitro Study

The present study was undertaken to develop a transdermal delivery device for melatonin and to determine the effects of system design on the release of melatonin. Melatonin(MT) diffusion characteristics from 2 solvents through a series of ethylene vinyl acetate membranes with 4.5%, 9%, 19%, 28% vinyl acetate were characterized using vertical Franz® diffusion cells. The solvent used were 40% (v/v) propylene glycol (PG) and 40%(v/v) propylene glycol with 30%(w/v) 2-hydroxypropyl-β-cytrodextrin. The best release rate (Jss = 0.795 μg/h/cm²) was obtained from the 40% PG vehicle through the 28% vinyl acetate membrane. Melatonin diffusion through this membrane with an acrylate pressure sensitive adhesive (PSA) with and without MT loading was also studied. The data revealed an interaction between MT and the PSA in the systems with MT-loaded adhesive. A MT transdermal delivery device was constructed based on the above data. Effect of storage time (1 day, 2 days, and 3 days) on the developed device was also investigated. Steady state flux values of MT did not vary significantly with storage time (p-value = 0.14). The steady state flux was 1.88 ± 0.6 μg/hr/cm²(n = 9). However, storage time did affect the burst effect of MT. Total amount of MT released in the first hour was 137.4 ± 25.7 μg after 3 days, 61.5 ± 8.9 μg after 2 days, and 43.8 ± 20.9 μg after 1 day.     

The effect of clove oil on the transdermal delivery of ibuprofen in the rabbit by in vitro and in vivo methods

The study was designed to evaluate skin permeation enhancement effect of essential oils from Eugenia caryophyllata (clove oil) in rabbits and to compare the in vitro absorption and in vivo permeation using ibuprofen as a model drug. The in vitro results indicated a significant permeation enhancement effect of the clove oil. The group with 1% oil appeared to the flux (239 μg/cm²/hr), and 3% oil was 293 μg/cm²/hr to some extent similar with 2% azone group (327 μg/cm²/hr). The enhancement ratio of clove oil was 7.3. In vivo results also demonstrated that clove oil showed a significant permeation enhancement effect, but the enhancement of clove oil was relatively weak than in vitro. The group with 3% oil exhibited the higher value of area under the curve (AUC) of 80.8 μg/mL·hr, which was 2.4 times the high of control. The AUC value of 3% oil group was similar to that of 2% azone group (89.8 μg/mL·hr). The GC-MS results indicated eugenol and acetyleugenol identified from clove oil might mainly contribute to enhance in vitro and in vivo absorption of ibuprofen because of its large quantities (90.93%).     

A novel apparatus for the determination of solubility in pressurized metered dose inhalers

The accurate solubility of salbutamol sulfate, budesonide, and formoterol fumarate dihydrate in hydrofluoroalkane propellant 134a at 25°C for 24 h, are reported. The authors describe a novel reusable in-line pressurized solubility apparatus containing an integral filter holder and a continuous decrimpable valve for the determination of drug/excipients solubility in pressurized metered dose inhalers. The solubility was determined by high-performance liquid chromatography. Solubility of salbutamol sulfate was determined as being below the detection limits while budesonide and formoterol fumarate dihydrate solubility were 23.136 ± 2.951 μg.g^-1 and 0.776 ± 1.023 μg.g^-1, respectively (n = 3). This novel solubility apparatus offers an improved ease of use and potential higher analytical throughput.     

Fabrication of robust Bi3.25La0.75Ti3O12 thin film resistant to hydrogen damage

Ferroelectric bismuth lanthanum titanate (Bi_3.25La_0.75Ti₃O₁₂; BLT) thin films were deposited on Pt/TiO₂/SiO₂/Si substrate by chemical solution deposition method. The films were crystallized in the temperature range of 600–700 °C. The spontaneous polarization (P_s) and the switching polarization (2P_r) of BLT film annealed at 700 °C for 30 min were 22.6 μC/cm² and 29.1 μC/cm², respectively. Moreover, the BLT capacitor did not show any significant reduction of hysteresis for 90 min at 300 °C in the forming gas atmosphere.     

Piroxicam benzoate--synthesis,HPLC determination,and hydrolysis

An improved method of piroxicam benzoate synthesis was described, and an isocratic reversed-phase high-performance liquid chromatography method for its determination was developed and fully validated. The method was found to be specific, precise (relative standard deviation 0.3%), accurate (mean recovery 99.9%), and robust. Limit of detection was estimated at 0.055 µg mL^-1 and limit of quantification at 0.185 µg mL^-1. The kinetics of piroxicam benzoate hydrolysis in aqueous buffer solutions (pH 1.1 and 10), simulated gastric and intestinal fluids was studied. The hydrolysis followed first-order kinetics. The following rate constants were obtained at pH 10: k = 1.8 × 10^-3 hr^-1 at 37°C and k = 3.4 × 10^-2 hr^-1 at 60°C. In acidic media, no significant hydrolysis was observed after 24 hr. During the 24-hr period in simulated intestinal fluid, only 10.9% of the starting ester was hydrolyzed.     

Optical absorption and nonlinear transmission of tetrahedral V (d) in yttrium aluminum garnet

The saturation of the optical absorption in V³⁺ : YAG crystal is investigated. The absorption cross section of tetrahedral V³⁺ at 1.08 μm is estimated to be 8.2±2.5x10^-18 cm². Q-switching and passive mode-locking for a number of solid state lasers with wavelengths at 747 nm, 780 nm, 1.06 μm and 1.34 μm have been obtained with a V³⁺ :YAG saturable absorber.     

Photoacoustic detection of water permeation through ultrathin films

The temperature-dependent equilibrium between water that is adsorbed at a solid surface and the water vapour in the surrounding gas gives rise to an additional signal in photoacoustic measurements. This is employed to determine the permeation resistance of water through ultrathin coatings of cadmium arachidate deposited onto a polymer substrate by the Langmuir-Blodgett dipping technique. It seems not to depend on the number of bilayers and is 0.35 s cm^-1 in the temperature region from 30 to 50 °C it increases to 0.7 s cm^-1 at 60 °C.     

Excited-state absorption at 1.57 μm in U:CaF2 and Co:ZnSe saturable absorbers

Appreciable excited-state absorption (ESA) in U²⁺:CaF₂ and Co²⁺:ZnSe saturable absorbers was measured at λ=1.573 μm by optical transmission versus light fluence curves of 30–40 ns long pulses. The ground- and excited-state absorption cross-sections obtained were (9.15±0.3)×10⁻²⁰ and (3.6±0.2)×10⁻²⁰ cm², respectively, for U²⁺:CaF₂, and (57±4)×10⁻²⁰ and (12.5±1)×10⁻²⁰ cm² for Co²⁺:ZnSe. Thus, ESA is not negligible in U²⁺:CaF₂ and Co²⁺:ZnSe, as previously estimated.     

Elastic stiffness and thermal expansion coefficients of various refractory silicides and silicon nitride films

The elestic stiffness parameter E_f/(1−ν_f) and the thermal expansion coefficient _f were obtained for four different silicides (TiSi₂, TaSi₂, MoSi₂ and WSi₂) and for two different nitrides (chemically vapor-deposited Nitrox Si₃N₄ and r.f. plasma SiN) from stress-temperature measurements on identical films deposited on two different substrate materials. The values determined for _f and E_f/(1−ν_f) were quite similar for all silicides and averaged 15 ppm °C⁻¹ and 1.1 × 10¹² dyncm⁻² respectively. The thermal mismatch of these silicides is such that, once safely formed, the silicide film should be able to withstand high temperature processing steps without cracking. For the nitrides the values were essentially the same (approximately 1.5 ppm°C^-1), although the larger value of E_f/(1−ν_f) chemically vapor-deposited Si₃N₄ film (3.7 × 10¹² as opposed to 1.1 × 10¹² dyn cm^-2) indicates that it is somewhat stiffer than the SiN film.