A 16-Mb Toggle MRAM With Burst Modes

This paper describes a recently developed 16-Mb toggle magnetic random access memory (MRAM). It has 100-MHz burst modes that are compatible with a pseudo-SRAM even though the toggle cell requires reading and comparing sequences in write modes. To accelerate operating clock frequency, we propose a distributed-driver wide-swing current-mirror scheme, an interleaved and pipelined memory-array group activation scheme, and a noise-insulation switch scheme. These circuit schemes compensate the toggle cell timing overhead in write modes and maintain write-current precision that is essential for the wide operational margin of MRAMs. Because toggle cells are very resistant to write disturbance errors, we designed the 16-Mb MRAM to include a toggle MRAM cell. The MRAM was fabricated with 0.13-mum CMOS and 0.24-mum MRAM processes with five metal layers.     

Formulation study of topically applied O/W lotion containing vitamin D3 derivative, focusing on skin permeability of the drug

Permeation of 22-oxacalcitriol-1α, 25-dihydroxyvitamin D(3) (OCT) through excited hairless mouse skin was determined after application of OCT as solutions and O/W lotions consisted of different polarities of solvents: medium-chain fatty acid triglyceride (MCT), myristate isopropyl (IPM), 1,3-butylene glycol (1,3-BG), and propylene glycol (PG). OCT concentration in skin was also followed after applying these formulations. A two-layer diffusion model was composed to analyze dermatopharmacokinetic profiles of OCT for each vehicle. In the OCT solutions, skin permeation profile of OCT differed depending on solvent polarity. The O/W lotion with a high MCT content led to a low amount of OCT in skin. On the other hand, the O/W lotion with a high 1,3-BG content led to a high amount of OCT in skin. This dermatopharmacokinetic analysis indicated that addition of MCT to the formulation decreases the skin/vehicle partition coefficient of OCT and increases the diffusion coefficient of OCT in skin. However, the opposite effects on these two parameters were found in the case of 1,3-BG. Thus, skin permeability of OCT differed depending on the solvents used in the formulation. These results indicate that skin permeability of OCT is influenced by the physicochemical properties (i.e. polarity) of OCT, solvent, and skin. Our findings on the solvent effects of the skin permeability of OCT are thus useful for designing topical drug formulation, especially in aiming for bioequivalent dosage formulas.     

Development of sustained-release tablets containing sodium valproate: in vitro and in vivo correlation

We have developed a 200 mg and 400 mg sustained-release sodium valproate tablet that allows effective blood concentration of the active drug with once-a-day dosing. The controlled dissolution or sustained release of the drug was attained by a membrane-controlled system. A single-coating system did not adequately control the dissolution rate, and therefore double-coated tablets were prepared and a human pharmacokinetic study was conducted. With the 200 mg VPA-Na tablets, the nonfasting C_max was only 20% higher than the fasting C_max. An in vitro dissolution test was conducted to predict the effects of food on drug dissolution after administration of this tablet. A relatively good correlation was observed between the absorption profiles and the dissolution profiles of the drug.     

Skin Permeation of Lidocaine from Crystal Suspended Oily Formulations

ABSTRACT

In vitro permeation of lidocaine (lidocaine base, LID) through excised rat skin was investigated using several LID-suspended oily formulations. The first skin permeation of LID from an LID-suspended oily solution such as liquid paraffin (LP), isopropyl myristate (IPM), polyoxyethylene (2) oleylether (BO-2), and diethyl sebacate (DES) was evaluated and compared with that from polyethylene glycol 400 (PEG400) solution, a hydrophilic base. The obtained permeation rate of LID, J_app, from PEG400, LP, IPM, BO-2, and DES was in the order of DES>BO-2 = IPM>LP>PEG400, and increased with LID solubility in the oily solvents, although LID crystals were dispersed in all solvents. Subsequently, oily formulations that consisted of different ratios of the first oily solvent (IPM, BO-2, or DES) (each 0–20%), the second oily solvent (LP) and an oily mixture of microcrystalline wax/white petrolatum/paraffin (1/5/4) were evaluated. BO-2 groups at a concentration of 5% and 10% had the highest J_app among the oily formulations, although a higher BO-2 resulted in lower skin permeation. In addition, pretreatment with BO-2 increased the skin permeation of LID. These results suggest that the penetration enhancing effect by the system may be related to the skin penetration of BO-2 itself. Finally, mathematical analysis was done to evaluate the effect of BO-2, and it was shown that BO-2 improved the LID solubility in stratum corneum lipids to efficiently enhance the LID permeation through skin.     

Drug Release Test to Assess Quality of Topical Formulations in Japanese Market

Three release test methods—watch glass method, rotating dialyses cell method, and disk assembly method (DA)—were assessed for use in a quality control procedure for four different semisolid topical formulations containing indomethacin (IDM). Although minor modification in the methods to optimize the release rate was necessary for each formulation, DA proved superior to the other two Methods and thus was used to assess the quality of topical formulations on the Japanese market. First, DA was used for a storage test of hydrophilic ointments and cataplasms; difference in the release profiles of IDM from these formulations showed changes with time, which suggests the usefulness of DA for checking lot-to-lot uniformity. Second, dermal patch and tape as transdermal delivery systems containing nitro-glycerin or isosorbide dinitrate were investigated. Since different sizes and shapes of these products are available, various assemblies of DA were required to Pt individual products. Different release patterns were obtained among the products for both drugs. These results suggest that DA is a simple, reproducible, and more useful quantitative release test for quality control of topical formulations.     

Difference in the enhancing effects of ultrasound on the skin permeation of polar and non-polar drugs

The effect of ultrasound (150 kHz, 111 mW/cm2) on the permeability of isosorbide dinitrate (ISDN) and antipyrine (ANP) through excised hairless rat skin was evaluated using an Arrhenius plot. The permeability coefficients of ISDN across skin (at various temperatures) in the presence and absence of ultrasound were virtually isolinear on the Arrhenius plot. It has been suggested that the temporal increase in the ISDN flux, which was observed when ultrasound was applied in our previous study, was only a result of the thermal effect of ultrasound, i.e., an increase in the temperature of the donor solution. On the other hand, ultrasound influenced the Arrhenius plot of ANP, suggesting that the enhancement effect for ANP permeation could be not explained only by the thermal effect of ultrasound. In addition, the effective diffusion (D) and partition coefficients (K) of ISDN and ANP were estimated using their skin permeation profiles across the ultrasonic pretreated skin. The coefficients of ISDN with ultrasonic pretreatment were comparable to those without pretreatment. On the other hand, the D value of ANP with ultrasonic pretreatment was increased about 4 times by ultrasonic pretreatment, in spite of an insignificant change in the K value. These results suggest that the ultrasound used in the present study increased the effective diffusivity across the aqueous region in the stratum corneum to enhance the skin permeation of the polar compound, ANP.     

Noncomplimentary rewriting and serial-data coding scheme forshared-sense-amplifier open-bit-line DRAM

A noncomplimentary rewriting scheme is proposed for open-bit-line DRAM's adopting a shared subsense amplifier. The scheme can theoretically cancel inter-bit-line coupling noise down to zero. In order to suppress the peak in unselected word line noise, a serial-data coding scheme was also developed, This scheme can reduce unselected word-line noise by at least 50%     

Observation noise and zero loci of the time series model

The properties of zeros of time series models are examined in a linear stochastic system with white Gaussian observation noise. Each zero has a locus in the complex plane as the variance of observation noise changes from zero to infinity. An application of zero loci is presented for understanding the properties of the autoregressive model     

Preparation and evaluation of liquid-crystal formulations with skin-permeation-enhancing abilities for entrapped drugs

The usefulness of liquid crystals (LC) in topical formulations for application to skin was evaluated by measuring the in vitro permeation profile of a model compound, calcein, entrapped in a LC formulation, through excised hairless rat skin and a three-dimensional cultured human-skin model; the viability was determined using the MTT assay. Two physically stable LCs were prepared from a mixture of mono-, di-, and tri-esters 1, and monoesters 2, composed of erythritol and phytanylacetic acid. Cryo-transmission electron microscopy (cryo-TEM), electron diffraction patterns, and small-angle X-ray diffraction (SAXS) observations of the LC nanodispersions showed that the structures of the LCs were reverse hexagonal (LC-A) and cubic (LC-B). The skin-permeation properties of calcein were enhanced by entrapping in the LCs as a result of the increase in calcein partition from the LC dispersion solution into the skin; the properties were analyzed using a skin-permeation-time profile. Drug partitioning could also be modified by the LC structure. No skin damage was caused by the LC formulation in these experiments.The present study suggests that LC dispersions are potential additives in topical drug formulations and cosmetic formulations.     

Effect of several hydrophilic polymers on the permeation of morphine and salicylic acid through excised hairless rat skin

Several hydrophilic polymers changed the cumulative amount of morphine (MOR) permeated through excised hairless rat skin from 1% MOR hydrochloride solution containing ethanol and l-menthol at concentrations of 40% and 5%, respectively, as permeation enhancers. Anionic polymers (carboxyvinylpolymer and methylvinylether-maleic anhydride copolymer) in the test solutions decreased the skin permeation of MOR, whereas cationic polymers (polyethyleneimine and chitosan) increased it, compared with that without polymers. Little change, however, was observed by the addition of nonionic polymers (hydroxypropylcellulose and polyethyleneoxide). On the other hand, the cationic and anionic polymers in the test solutions decreased and increased, respectively, the skin permeation of salicylic acid (SA) from the same enhancing system containing sodium salicylate. These opposite results were probably caused by the change in escaping tendency of the drugs from the vehicles, which was due to the drug-polymer interaction. (The escaping tendency has a great effect on the drug partition from the polymer solution to the skin barrier). The effect of hydrophilic polymers on the partition was then evaluated by Donnan membrane theory. The partition of MOR was increased and decreased by the presence of polymers having identical and opposite charge to MOR. The low partition of the drugs to skin may also be caused by low diffusion of the drugs in the polymer solutions. The drug release from the hydrophilic polymer solutions was then measured, and the release rate was found to have decreased in the presence of polymers having opposite charge to MOR and SA. It is suggested that these drug-polymer interactions changed the drug partition to skin thus changing the skin permeation of the drug.