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Publication number | US5147296 A |
Publication type | Grant |
Application number | US 07/751,276 |
Publication date | Sep 15, 1992 |
Filing date | Aug 28, 1991 |
Priority date | Oct 3, 1988 |
Fee status | Paid |
Publication number | 07751276, 751276, US 5147296 A, US 5147296A, US-A-5147296, US5147296 A, US5147296A |
Inventors | Felix Theeuwes, J. Richard Gyory, Ronald P. Haak |
Original Assignee | Alza Corporation |
Export Citation | BiBTeX, EndNote, RefMan |
Patent Citations (23), Non-Patent Citations (2), Referenced by (86), Classifications (5), Legal Events (3) | |
External Links: USPTO, USPTO Assignment, Espacenet | |
This application is a divisional of U.S. patent application Ser. No. 252,402 filed Oct. 3, 1988, now U.S. Pat No. 5,080,646.
This invention relates to electrotransport agent delivery. More particularly, this invention relates to a membrane capable of controlling the release of agent from an electrotransport agent delivery system where passive delivery is inhibited but not delivery under an electric current. Still more particularly, but without limitation thereto, this invention relates to a membrane suitable for use in the in vitro testing of release rates of electrotransport agent delivery devices.
Many drugs are not suitable for passive drug delivery because of their size, ionic charge characteristics and hydrophilicity. One method of overcoming this limitation in order to achieve transdermal administration of such drugs is the use of electrical current to actively transport drugs into the body, as for example, through intact skin. This concept is based upon basic principles of electrochemistry. An electrochemical cell in its simplest form consists of two electrodes and associated half cell reactions, between which electrical current can flow. Electrical current flowing through the metal portion of the circuit is carried by electrons (electronic conduction), while current flowing through the liquid phase is carried by ions (ionic conduction). Current flows as electrical charge is transferred to chemical species in solution by means of oxidation and reduction charge transfer reactions at the electrode surfaces. A detailed description of the electrochemical processes involved in electrically-assisted drug transport can be found in electrochemistry texts such as J. S. Newman, Electrochemical Systems (Prentice Hall, 1973) and A. J. Bard & L. R. Faulkner, Electrochemical Methods, Fundamentals and Applications (John Wiley & Sons, 1980). Therefore, only pertinent portions will be presented here.
Electrically-assisted transport or electrotransport, is defined as the mass transport of a particular chemical species in the presence of an electric potential. Typically, said transport is through a biological interface or membrane when the electrical potential gradient is imposed across it. Three physical processes contribute to transport under these conditions: passive diffusion, electromigration and convection.
The Nernst-Planck equation (1) expresses the sum of these fluxes for any particular chemical species i in the presence of an electrical field, ∇Φ.
Ji =-[Di ∇Ci ]-[zi F ui Ci ∇Φ]+[Ci v] (1)
Ji =flux of species i (moles/cm2 -sec)
Di =diffusion coefficient of i (cm2 /sec)
∇=the gradient operator
Ci =concentration of i
zi =number of charges per molecule of i
F=Faraday's constant (96,500 coulombs/mole of charge)
ui =mobility of i (velocity/force=sec/g)
Φ=electrical potential (volts)
v=velocity vector (cm/sec)
The Nernst-Plank equation (1) has three terms, one for each of the physical processes contributing to the mass transport. The first term is the flux due to passive diffusion and is proportional to the concentration gradient of species i. The second term is the flux due to electromigration, where the driving force is the gradient of electrical potential, i.e., the electric field strength. The third term is the flux due to convection or electroosmosis, where the mechanism of transport is the movement of material by bulk fluid flow which is determined by the magnitude and direction of the bulk fluid velocity vector.
Considering transport in only one direction of a rectilinear coordinate system, equation (1) may be simplified to:
Ji,x =-[(Di) (dCi /dx)]+[zi F ui Ci Ex ]+[Ci vx ] (2)
Ji,x =the total electrically-assisted flux of species i in the x direction
Ex =-(dΦ/dx)=the electrical field in the x direction i.e. the negative of the electrical potential gradient
vx the x component of the velocity vector
Equation (2) applies within each and every phase, and the physical constants and extensive properties must be applicable to the phase of interest. For the case of an electrotransport transdermal system positioned on the skin, one form of equation (2) holds within the drug containing reservoir of the electrotransport system where Di, ci, ui, etc., are the diffusion coefficient, concentration and mobility of species i within the system. Another identical form of equation (2) holds within the skin (assuming the skin is uniform) except that the diffusion coefficient, concentration and mobility of species i are now those within the skin. The extensive properties of these equations such as the concentration and electric field strength are linked at the interface by an appropriate proportionality constant such as the partition coefficient and the ratio of dielectric constants, respectively.
The second term in equation (2) describes the flux due to electromigration. Typically written in terms of the electrical field, it is often more convenient to express electromigration in terms of the electrical current. By using the transference number of species i, ti, which is the fraction of current carried by species i, the electromigration flux of species i, Ji,EM, may be expressed as the product of the transference number and the current density passing through the medium:
Ji,EM =[(ti) (I)]/A (3)
I=the total current passing through the medium
A=the area through which the current passes
The third term in equation (2) describes the flux due to convection. Disregarding the possibility of significant hydrostatic pressure gradients across the membrane or chemical osmosis driving forces, and assuming the membrane has a fixed surface charge, it can be said that the only means of moving an appreciable amount of fluid across a membrane is through electroosmosis. Electroosmosis is defined as bulk fluid flow entrained by the migration of unpaired excess ions moving in response to an applied electric field. The electroosmotic flux of species i, Ji,EO, is related to the total current passing through the membrane by the following equation:
Ji,EO =(εζI)/(κ�μA) (4)
ε=the dielectric constant of the liquid medium
ζ=the zeta potential of the membrane having a fixed charge
κ�=the conductivity of the liquid phase
μ=the viscosity of the liquid phase
Equations (3) and (4) demonstrate that the second and third terms of equation (2) may be written as functions of the total current passed through a system. Hereinafter, the sum of these two terms will be referred to as the electrokinetic flux, JEK.
As stated earlier, the first term of equation (2) is the passive diffusion term. This term is identical to that when passive diffusion is the only mechanism of mass transfer, i.e., it is independent of the electrical conditions of the system. This term will hereinafter by referred to as the passive flux component, Jp. The sum of all three terms in equation (2) will be called the electrically-assisted flux, JEA :
Since the electrokinetic flux, JEK, is the sum of the flux due to electromigration and the flux due to electroosmosis, equation (5) can be simplified to:
A membrane which mimics the behavior of skin must exhibit the following mass transport properties: transport by convection should be negligible at high ionic strength, resistance to passive diffusion should be high, and resistance to electromigration should be relatively low. Ideally, when no electric field is imposed on the membrane, i.e., no current is passed across the membrane, no drug flux should be detected. When a field is applied and current is caused to flow across the membrane, appreciable drug flux should be detected. Furthermore, a relative small voltage should be required in that a 100 μA/cm2 current would require less than 1 volt.
The concept of electrotransport in drug delivery is known, and there are a number of categories in which drug delivery systems utilizing electrotransport principles can offer major therapeutic advantages. See P. Tyle & B. Kari, "Iontophoretic Devices" in DRUG DELIVERY DEVICES, pp. 421-454 (1988). There is a continuing need to develop systems with improved characteristics, specifically improved control of the drug delivery. State of the art rate controlling membranes such as are taught in U.S. Pat. No. 3,797,494, are suitable for passive transport but do not provide control over electrically-assisted delivery. Therefore, there is a need for a membrane which may be used to limit or control the electrically-assisted release from the system. Further, there is a need for an electrotransport drug delivery system which has a control membrane to inhibit the release of drug from the system when no current is flowing. The main feature is that use of such a membrane, by eliminating or greatly reducing passive transport, would allow release of the drug to be turned on and off, by simply turning the electric field (current) on and off.
Such a membrane would also provide a safety feature to prevent excess drug delivery from occurring if the electrotransport system is placed on abraded skin or on a body surface which has somehow been compromised. Further, such a safety feature would inhibit drug release during handling of the system.
Along with the growing interest in the development of electrotransport systems, there is a growing need for improved techniques of testing the properties of said systems. For example, state of the art techniques for measuring the in vitro release rates of passive transdermal systems are inadequate for testing electrotransport systems. Typically, such testing utilizes a synthetic membrane such as Hytrel� or an ethylene vinyl acetate copolymer such as EVA 9, which exhibit characteristics similar to that of skin during passive drug diffusion. There is a need for a synthetic membrane that exhibits electrically-assisted ionic transport properties similar to that of skin.
Another use for such a membrane would be for system stability testing. Human cadaver skin cannot be used for this application because of the extent of natural donor to donor variation and large supplies are often needed for quality control, which are not always readily available. For stability testing, a membrane must behave consistently over time in order to provide an accurate measure of system stability.
An object of this invention is to provide an improved approach and means for providing system control within an electrotransport agent delivery system.
Another object of this invention is to provide for electrically-assisted delivery of agents with a safety mechanism to insure that agent is only released during those periods when the current is on.
A still further object of this invention is to develop a membrane which will allow passage of agent when under the influence of an electric current and which will also be a barrier to the passage of the same agent when not under the influence of an electric current, for use as release rate controlling membranes or as separator membranes.
Another object of this invention is to develop a membrane model for skin having consistent and reliable transport properties, to provide the capability for performing accurate measurements of the in vitro release rate of drug from electrotransport delivery systems, and to perform system stability studies.
These and other objects, features and advantages of the invention have been demonstrated by the present invention wherein an electrotransport agent delivery system for placement on a body surface is comprised of: a backing member; a source of electrical power; a first and a second current conducting member; a reservoir means containing an agent to be delivered; means for maintaining said system in current conducting and agent transmitting relationship to said body surface; and a means for controlling agent delivery positioned between said reservoir means and said body surface.
The invention will be described in further detail with reference to the accompanying drawings wherein:
FIG. 1 is a schematic cross sectional view of the membrane of this invention incorporated into an electrotransport transdermal therapeutic system having a peripheral adhesive layer, where electrical power is supplied by an integral power source;
FIG. 2 is a top view of the embodiment of FIG. 1;
FIG. 3 is a schematic cross sectional view of the membrane of this invention incorporated into another electrotransport transdermal therapeutic system;
FIG. 4 is a perspective view of an embodiment of the invention incorporated into a single electrode unit;
FIG. 5 is a schematic cross sectional view of the membrane of this invention when used as a separator;
FIG. 6 is a graph comparing the electrically-assisted and passive flux of metoclopramide through membranes of this invention having various resin loadings; and
FIG. 7 is a graph illustrating the effect of resin loading on the JEK /JP ratio of metoclopramide through various membrane compositions of this invention.
The composite membrane of this invention exhibits larger electrically-assisted transport than passive. When no current flows through the system, passive drug diffusion from the system is negligible or insignificant. The method of evaluating suitable composite membranes consists of determining the electrokinetic and the passive flux of a compound through the membranes and using their ratio as a measure of the ability of these membranes to behave as required.
Passive transport of ionic compounds may be eliminated entirely by a hydrophobic membrane. However, the electrical resistance of such a membrane is prohibitively high. In order to reduce electrical resistance, some hydrophilic pathways must be provided but not so many that passive diffusion is large. This may be done by use of a microporous membrane having a few continuous aqueous paths, or by use of an ion exchange membrane. This invention is a composite membrane having properties of both types of membranes wherein a hydrophilic resin, such as an ion exchange resin, is blended into a hydrophobic polymeric matrix. The resin has a high permeability for agent and provides a complex of "microporous" ion exchange pathways. The hydrophobic polymer has a low permeability for agent and provides a non-permeable hydrophobic matrix structure. The membrane can be manufactured by solvent casting, melt processing or extrusion.
A microporous membrane limits diffusion simply by limiting the number of pathways available. Ion exchange membranes limit diffusion by a more complex mechanism. Ion exchange membranes have either a fixed negative or a fixed positive charge. The fixed charge is compensated by unbound or covalently bound compounds having the opposite charge, i.e., counter- or co-ions. The fixed charge is bound to the membrane and is not free to move, thereby causing the entire membrane to be charged and inhibiting ions of like charge from passing through the membrane. Maintenance of electroneutrality prevents the co-ion from passively diffusing. Therefore, passive diffusion of ionic compounds is prevented because one of the ions can not penetrate the membrane.
Rejection of a particular ion occurs when the fixed charge on the membrane has the same sign as the ion. When current is passed, the ions having a charge opposite to that of the fixed charge of the membrane, will have a higher transference number through the membrane than will the ions having the same charge as the membrane. Therefore, an anion exchange membrane having a positive fixed charge may exhibit very low passive transport of a positively charged species, but the electrically-assisted transport of that species may also be low. Conversely, a cation exchange membrane having a negative fixed charge may have a higher passive transport of positively charged species, but it will also exhibit larger electrically-assisted transport of these species. It is not obvious which of these membrane types will exhibit the best JEK /JP ratio (the ratio of the electrokinetic to the passive flux) in this situation.
We have found that by blending a small amount of resin within a hydrophobic matrix, the total water content and density of hydrophilic pathways through an otherwise hydrophobic membrane, may be controlled. Also, the charge density within these pathways remains relatively high, which would not occur if the hydraulic permeability of a normal ion exchange membrane was controlled by merely changing the fixed charge density within the membrane.
Upon further analysis of the composite membranes of this invention, we have found that the process of blending a small amount of hydrophilic resin within a hydrophobic matrix actually enhances the JEK /JP ratio of the membrane. The passive flux of the species of interest for a unit area of pure ion exchange resin and pure hydrophobic matrix material is given by the expressions JRP and JMP, respectively. For a membrane having a uniform dispersion of resin within matrix material, the fraction of surface area which is resin material is identical to the volume fraction of resin within the membrane. Therefore, the passive flux per unit area of composite membrane, JP, is given by:
where H is the volume fraction (area fraction) of ion exchange resin based on the total volume of the composite membrane.
It may be assumed that when current is passed, only the volume occupied by the ion exchange resin will contribute to the electrokinetic flux, JEK, i.e., there is no ionic conduction or electroosmotic flow through the hydrophobic matrix material. Therefore, the electrokinetic flux may be written as:
JEK =([(tD) (I)]/A)+[(εζI)/(κ�μA)](8)
where tD is the transference number of the drug through the ion exchange resin. Equation (8) shows that the electrokinetic flux based upon unit area of composite membrane is independent of the volume fraction of resin. Even though the flux may be independent of loading, the voltage required to achieve the specific current, I, is not. As resin loading is decreased, the voltage required to pass the specific current will increase. This follows from Ohm's Law V=IR, where as loading increases the resistance (R) increases since R is an area independent term, thus increasing the voltage (V).
The ratio of the electrokinetic to the passive flux is determined by: ##EQU1## If the solution next to this composite membrane has a relatively high ionic strength then the electroosmotic component of equation (9) will be small. Also, if the passive diffusion of the drug is small through the hydrophobic matrix compared to that through the ion exchange portion of the composite membrane, the term in the denominator involving JMP may also be eliminated. Therefore, the electroosmotic and matrix passive diffusion terms may be eliminated from equation (9). Yet another substitution may be made, specifically,, the passive flux through the resin may be written in terms of the diffusion coefficient and concentration gradient. Assuming that the drug concentration on the receptor side of the membrane is essentially zero and that the concentration gradient within the membrane is linear, JRP, may be written as:
D=the diffusion coefficient of the drug through the resin
CD =the drug concentration in the resin on the donor side of the membrane
l=the thickness of the membrane
Therefore, equation (9) can be simplified to:
JEK /JP =(tD I l)/(H D CD A) (11)
This simplified form indicates that JEK /JP is inversely proportional to the volume fraction of resin, and therefore, the JEK /JP ratio should increase as the resin loading is decreased. From equation (11), it also can be predicted that thicker membranes should exhibit a larger JEK /JP ratio since the passive flux would decrease for thicker membranes without affecting the electrokinetic flux. However, a higher voltage would be required. The only direct influence electromigration has on the JEK /JP ratio is through the transference number of the drug. This number is preferably maximized and therefore, an ion exchange resin having a fixed charge of opposite charge than that of the drug species of interest, is desirable.
Equation (11) also indicates that it may be advantageous to operate at a low donor drug concentration. However, the transference number, tD, also depends on the drug concentration, but it is not a linear dependence. For large transference numbers, tD is nearly independent of concentration. However, for small transference numbers, tD is linearly dependent on donor concentration. Therefore, reducing the donor drug concentration will only increase the JEK /JP ratio if the transference number of the drug through the resin is high. Equation (11) also suggests a convenient means of characterizing membranes comprised of various materials since the JEK /JP ratio is predicted to be inversely proportional to the resin loading.
The only other piece of information required to determine the utility of a particular combination of materials is the resistance the membrane provides against electrokinetic transport. This may be measured by placing a reference electrode on either side of a membrane while current is being passed and recording the potential difference with an electrometer. The resistance of a membrane used for system testing is not a critical factor because power consumption is of little consequence for testing purposes. However, for use in an actual system, low resistance is critical. It is desirable to limit the voltage requirements imposed by a control membrane to be less than 1 volt at a current density of 100 μA/cm2, i.e., the membrane resistivity should be less than 10 kΩ-cm2.
Control membranes can be fabricated using a variety of suitable hydrophobic polymeric materials, including without limitation, polycarbonates, i.e., linear polyesters of carbonic acids in which carbonate groups recur in the polymer chain by phosgenation of a dihydroxy aromatic such as bisphenol A, polyvinylchlorides, polyamides such as polyhexamethylene adipamide and other such polyamides commonly known as "nylon", modacrylic copolymers such as those formed of polyvinylchloride and acrylonitrile, and styrene-acrylic acid copolymers, polysulfones such as those characterized by diphenylene sulfone groups in the linear chain thereof, halogenated polymers such as polyvinylidene fluoride and polyvinylfluoride, polychloroethers and thermoplastic polyethers, acetal polymers such as polyformaldehyde, acrylic resins such as polyacrylonitrile , polymethyl methacrylate and poly n-butyl methacrylate, polyurethanes, polyimides, polybenzimidazoles, polyvinyl acetate, aromatic and aliphatic polyethers, cellulose esters such as cellulose triacetate, cellulose, collodion, epoxy resins, olefins such as polyethylene and polypropylene, porous rubber, cross-linked poly(ethylene oxide), crosslinked polyvinylpyrrolidone, cross-linked poly(vinyl alcohol); derivatives of polystyrene such as poly (sodium styrenesulfonate) and polyvinylbenzyltrimethyl-ammonium chloride, poly(hydroxyethyl methacrylate), poly(isobutyl vinyl ether), polyisoprenes, polyalkenes, ethylene vinyl acetate copolymers, particularly those having 1-40 weight percent vinyl acetate content, such as those described in U.S. Pat. No. 4,144,317, incorporated herein by reference, polyamides, polyurethanes, polyethylene oxides, polyox, polyox blended with polyacrylic acid or Carbopol�, cellulose derivatives such as hydroxypropyl methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, pectin, starch, guar gum, locust bean gum, and the like, along with blends thereof. This list is merely exemplary of the materials suited for use in this invention. A more extensive list can be found in J. R. Scott & W. J. Roff, Handbook of Common Polymers (CRC Press, 1971) and in patents disclosing suitable materials for use in manufacturing microporous membranes such as U.S. Pat. No. 3,797,494, incorporated herein by reference.
Suitable hydrophilic resins include materials such as crosslinked polyvinylpyrolodone. Particularly suitable hydrophilic materials are ion exchange resins having ion exchange functional groups such as sulfonic acid, carboxylic acid, iminodiacetic acid and quaternary amines. These include, without limitation, the commercially available cation and anion resins listed below. Selection of an ion exchange resin is determined by the charge of the drug being delivered.
__________________________________________________________________________NAME SIZE DRY RESIN BED MOISTURE PORE(BACKBONE) FORM mesh meq/g meq/mL % of total SIZE__________________________________________________________________________Cation Exchange ResinsAG 50W-X12* H 100-200 5 2.3 42-48 small(Sulfonic acid)Bio-Rex �70* Na 200-400 10.2 3.3 65-74 large(Carboxylic acid)Chelex �100* Na 100-200 2.9 0.7 71-76 largeChelating resin(Iminodiacetic acid)Amberlite H 20-50 5.0 1.8 49-55 mediumIR-120**(Sulfonic acid)Anion Exchange ResinsAG 1-X8* Cl 20-50 3.2 1.4 39-45 medium(R4 N+)Amberlite Cl 20-50 3.3 1.2 42-48 mediumIRA-400**(RN(CH3)3 +)__________________________________________________________________________ *represents Trademark names of BioRad **represents Trademark names of Mallinckrodt
The incorporation of composite membranes according to this invention into electrotransport agent delivery systems, along with providing system control, also provide an important safety feature. The passive release of drug from a system which does not have such a control membrane can be vary high. This is normally not a problem, since the hydrophilic compounds delivered using such systems do not easily penetrate the skin via passive diffusion, i.e., the skin itself is a blocking membrane. However, if the skin is compromised in some manner, such as being cut or scraped, a harmful dose of drug could be delivered. When a composite membrane according to this invention is incorporated into an electrotransport system, the passive release of drug from the system is inhibited. In a system having such a membrane, the release of drug from the system would be predominantly controlled by the magnitude of the electrical current. Therefore, even if the skin is compromised, the amount of drug released from the system will be controlled to some tolerable level.
It is believed that this invention has utility in connection with the delivery of drugs within the broad class normally delivered through body surfaces and membranes, including skin, mucosa and nails. As used herein, the expressions "agent" and "drug" are used interchangeably and are intended to have their broadest interpretation as any therapeutically active substance which is delivered to a living organism to produce a desired, usually beneficial, effect. In general, this includes therapeutic agents in all of the major therapeutic areas including, but not limited to, anti-infectives such as antibiotics and antiviral agents, analgesics and analgesic combinations, anesthetics, anorexics, antiarthritics, antiasthmatic agents, anticonvulsants, antidepressants, antidiabetic agents, antidiarrheals, antihistamines, anti-inflammatory agents, antimigraine preparations, antimotion sickness preparations, antinauseants, antineoplastics, antiparkinsonism drugs, antipruritics, antipsychotics, antipyretics, antispasmodics, including gastrointestinal and urinary, anticholinergics, sympathomimetrics, xanthine derivatives, cardiovascular preparations including calcium channel blockers, beta-blockers, antiarrythmics, antihypertensives, diuretics, vasodilators, including general, coronary, peripheral and cerebral, central nervous system stimulants, cough and cold preparations, decongestants, diagnostics, hormones, hypnotics, immunosuppressives, muscle relaxants, parasympatholytics, parasympathomimetrics, proteins, peptides, polypeptides and other macromolecules, psychostimulants, sedatives and tranquilizers.
We have demonstrated the utility of this invention in connection with the delivery of metoclopramide. It is anticipated that this invention will prove to be useful in the controlled delivery of baclofen, betamethasone, beclomethasone, doxazosin, droperidol, fentanyl, sufentanil, leuprolide, lidocaine, methotrexate, micanazole, prazosin, piroxicam, verapamil, tetracaine, diltiazam, indomethacin, hydrocortisone, terbutaline and encainide. It is preferable to use the most water soluble form of the drug or agent to be delivered, which in most instances is the salt form.
The membrane of this invention is suited to control both the release of agent from electrodes or electrotransport systems. This application for our invention is best understood with reference to the accompanying drawings. In general terms, this invention can be used in conjunction with any state of the art electrotransport delivery systems such as those described in U.S. Pat. Nos. 4,325,367; 4,474,570; 4,557,723; 4,640,689; and 4,708,716; all of which are incorporated herein by reference. Similarly, this invention can be utilized with any state of the art electrodes which are attached to an external power source, such as those described in U.S. Pat. Nos. 4,274,420; 4,391,278; 4,419,092; and 4,702,732; all of which are incorporated herein by reference. The composite membrane of this invention can be manufactured as an integral part of a system or it can be manufactured separately with adhesive layers or some suitable means for adhering so that it may subsequently be affixed to any state of the art electrode or electrotransport system.
FIG. 1 is a typical example of an electrotransport system utilizing the composite membrane of this invention. System 10 has two current conducting members, referred to herein as a donor electrode 12 and a counter electrode 14. The electrodes can be metal foils, metal powder in a polymeric matrix, or any other electrically conductive material. The donor and counter electrodes are positioned adjacent to the donor electrode pad 16 which contains the agent to be delivered, and counter electrode pad 18, respectively. The pads can be polymeric matrices or gel matrices, for example, and are separated by an insulator 20 made of a non-conducting polymeric material. The system has a backing layer 22 made of an electrically insulating or nonconductive material such as is commonly used in transdermal systems. Electrical power is supplied by power source 24 which can be a battery or a series of batteries positioned between the electrodes 12 and 14 such that the electrode 12 is in direct contact with one pole of the power supply and electrode 14 is in direct contact with the opposite pole. The system adheres to the body surface 26 by means of a peripheral adhesive layer 28. The system would normally include a strippable release liner, not shown.
Composite membrane 30 is positioned between the donor electrode pad 12 and the body surface 26, so as to control drug release from the pad. In one type of electrotransport system, the donor electrode pad 14 contains the drug (salt form) to be delivered and the counter electrode pad 16 contains a suitable electrolyte. Another type of electrotransport system places drug in both electrode pads and in that manner both pads would function as donor electrode pads. For example, positive ions could be introduced into tissues from the anode (positive electrode), while negative ions could be introduced from the cathode (negative pole). In that instance, layer 32 positioned between the counter electrode pad 18 and the body surface 26 would also be a composite membrane.
Layer 34 is a barrier to avoid transference of ions across the body surface, and can be an air gap, a non-ion conducting adhesive or other suitable barrier to ion flow. The composite membrane of this invention can also be used in a system embodiment where layers 32 and 34 are omitted and instead, the counter electrode pad 18 and insulator 20 are designed so as to be in direct contact with the body surface 26.
FIG. 2 illustrates a top view of the system of FIG. 1 to show the parallel alignment of the components. In this configuration, the composite membrane 30 is rectangular in shape. However, this invention contemplates use in systems which have their components aligned peripherally, in a circular configuration for example, and the composite membrane would be designed accordingly.
The size of the composite membrane of this invention can also vary with the size of the system or electrode involved and can be within the range of from less than 1 cm2 to greater than 200 cm2. The average system however, has a size within the range of about 5-50 cm2. Similarly, the composite membrane will likely be within that range.
FIG. 3 illustrates another type of electrotransport system 36 suitable for use with the composite membrane 30 of this invention. System 36 has an agent reservoir 38 which can be in the form of a flexible bag as shown or a matrix as in system 10; a first current conducting membrane 40 positioned between reservoir 38 and battery 42; and a second current conducting member 44 positioned between reservoir 38 and a conductive backing member 46. The system has an insulating member 48 and a peripheral ion-conducting adhesive 50. The system is packaged with a strippable release liner 52. Suitable system materials are disclosed in U.S. Pat. No. 4,713,050, incorporated herein by reference.
FIG. 4 illustrates an electrode 54 suitable for use with the composite membrane 30 of this invention. Electrode 54 has a current conducting member 56, an agent reservoir 58 and composite membrane 30. The electrode adheres to the body surface by means of an ion-conducting adhesive layer 60. The electrode 54 has a fastener 62 by which it can be connected to an external current supply. Suitable electrode materials are disclosed in U.S. Pat. No. 4,274,420, incorporated herein by reference.
The membrane of this invention may also be used to keep the electrolyte and agent somewhat separated during storage. This is shown in FIG. 5. Since the composite membrane 30 inhibits release from a delivery system when no electrical current is flowing, it will also function to inhibit release from a reservoir within a delivery system. In FIG. 5, reservoir 64 contains electrolyte and reservoir 66 contains the agent to be delivered. Membrane 30 serves to minimize the passage of components from reservoir 64 into reservoir 66 and vice versa. Once the electrical current begins to flow, the components of reservoir 64 are free to move across membrane 30.
Composite membranes according to this invention can also be used for the in vitro evaluation of agent or drug release rates of electrotransport systems. In order to perform such an evaluation using a synthetic membrane, the membrane must have electrically-assisted transport characteristics similar to that of human skin where the passive transdermal permeation rate for hydrophilic compounds is often very low compared to the electrically-assisted permeation rate. The membrane of this invention meets such requirements.
An evaluation of the agent release characteristics of an electrotransport system using a composite membrane according to this invention involves the placement of the complete system on the surface of the composite membrane, adequately supported underneath, having a reservoir of receptor solution positioned on the opposite side of the membrane. If no such controlling membrane was used, i.e., if a microporous membrane was employed, then agent would quickly be released from the system via passive diffusion. When a composite membrane according to this invention is used for the test, the passive transport of agent into the receptor solution is inhibited. When the electrotransport system is placed in contact with the composite membrane, electrical current can flow, thus providing electrically-assisted transport of agent into the receptor solution.
The testing can provide several important system characteristics including, the amount of agent contained in the system, the magnitude of electrical current flowing through the system, the agent discharge profile as a function of time, and the discharge capacity of the electrical power source.
Having thus generally described our invention, the following examples will illustrate how variations of the above described parameters provide therapeutically effective electrotransport systems.
Commercially available polypropylene and polyethylene based microporous membranes (Cellgard� manufactured by Celanese), polycarbonate and polyester microporous membranes (Nuclepore�), cellulose and cellulose acetate membranes with varying amounts of triacetin and a porous glass material (Vycor�, Corning No. 7930) were cut to the appropriate size and used as supplied. Pore sizes ranged from 40 Å for the porous Vycor� to 0.2 μm for Cellgard� and were undetermined for the cellulose based materials.
The transport properties of these membranes were evaluated by measuring the passive and electrically-assisted flux of metoclopramide (MCP) across each membrane. This was done using a two compartment cell. Drug solution was placed in the anode (donor) compartment and the cathode (receptor) compartment solution was periodically sampled and evaluated for MCP content. The donor solution was 0.1 g MCP/g water. The receptor solution was Dulbecco's phosphate buffered saline (DPBS), a mixture of salts made to mimic interstitial fluids with a total salt concentration of 0.15M and the pH adjusted to 7. DPBS is commercially available from Gibco. The experimental temperature for all experiments was 32� C. Cells operating under passive conditions had zero current applied while cells operating under active or electrically-assisted conditions had 100 μA/cm2 applied such that positive ions migrated from the donor to the receptor compartment and negative ions migrated from the receptor to the donor compartment. In this manner, the electrode next to the donor solution was the anode and that next to the receptor solution was the cathode. At sampling time, all of the receptor solution was removed and replaced with fresh DPBS. The samples were analyzed for MCP content using UV-absorbance at 310 nm.
None of the commercially available microporous membranes evaluated provided satisfactory results. Either current could not be passed through the membrane, as for some of the Cellgard� and cellulose acetate membranes, or the passive transport of MCP greatly outweighed the electrokinetic transport, thereby making the measured flux with and without applied current indistinguishable.
Commercially available ion exchange membranes evaluated were of the strong acid or strong base type. They were cut to size and then soaked in a saturated sodium chloride solution. This pretreatment ensured that the co-ion of the membranes fixed charge would be either sodium or chloride. The transport properties of these materials were evaluated as in Example I. The anion exchange membranes tested were Raipore 1030, Raipore 4030 and Raipore 5030. These showed no appreciable difference in MCP flux for either passive or electrically-assisted transport. The cation exchange membranes tested were Nafion�, Raipore 1010, Raipore 4010 and Raipore 5010. Nafion� and Raipore 5010 exhibited very small steady state MCP fluxes. The flux of MCP through Raipore 1010 indicated that the passive component exceeded the electrokinetic component to a large degree and therefore, both electrically-assisted and passive fluxes were comparable. The only membrane to show any significant difference between electrically-assisted and passive transport, was Raipore 4010. The Raipore 4010 exhibited a lag time on the order of 3 hours, which is desirable for certain drug delivery patterns.
Composite membranes according to this invention were made using the following materials. Three resins were used: cross-linked polyvinylpyrolodone (PVP-xl), a wettable resin which picks up a slight positive charge due to hydrogen ion adsorption at amine sights, BioRex�70, a macroreticular acrylic polymer based carboxylic acid cation exchange resin made by Bio-Rad Laboratories, and Chelex�100, a styrene divinylbenzene lattice with paired iminodiacetate cation exchange groups also made by Bio-Rad Laboratories. Two particle sizes of Chelex�100 were used, <400 mesh and 100-200 mesh. All films containing PVP-xl were made with ethylene vinyl acetate having a 28 weight percent vinyl acetate content (EVA 28) as a matrix material. Membranes containing Bio-Rex�70 and Chelex�100 were made with ethylene vinyl acetate having a 40 weight percent vinyl acetate content (EVA 40) as a matrix material. Membranes were made by solvent casting or melt processing. All membranes containing PVP-xl were made by standard melt processing techniques and all membranes containing Bio-Rex�70 were solvent cast from methylene chloride and dried at ambient conditions. Both methods of preparation were used for membranes containing Chelex�100. The transport properties of these composite membranes were evaluated as in Example I.
Electrically-assisted and passive flux profiles of MCP through three volume loadings of Bio-Rex�70 in EVA 40 are shown in FIG. 6. Steady state was quickly achieved and a clear separation of electrically-assisted and passive transport was observed. Both electrically-assisted and passive steady state transport rates increased with increased resin loading.
The following table presents the JEK /JP ratios for several of the membranes tested. The data represents the average steady state flux values.
TABLE I______________________________________Polymer Resin Resin Loading, vol % JEK /JP Ratio______________________________________EVA 40 Bio-Rex �70 17.4 6 22.9 2.5 33.8 1EVA 28 PVP-x1 12 6.4 18 0.9 25 0.4 34 0.3EVA 40 Chelex �100 18.5 45 � 17 (100-200 mesh) 24.2 20 � 3 46.4 18 � 3______________________________________
Except for the 34 volume percent PVP-xl in EVA 28, the general trend was as the loading increased, so did the passive transport rate, while the electrokinetic transport remained relatively unchanged. Therefore, the JEK /JP ratio decreased with increasing resin loading. The observed trend over the range of resins and volume loadings tested, was that for equivalent resin loadings, Chelex�100 exhibited larger JEK /JP ratios than Bio-Rex�70, which in turn was better than PVP-xl. Both Chelex�100 and Bio-Rex�70 are cation exchange resins whereas PVP-xl will pick up a slight positive charge and act as an anion exchange resin. Since MCP is a positively charged drug, it was expected that MCP would have a larger transference number through anion exchange resins and therefore, a larger JEK /JP ratio in Chelex�100 and Bio-Rex�70 membranes. Interestingly, Bio-Rex�70 has a higher fixed charge density than Chelex�100, yet it exhibited lower JEK /JP ratios. We believe that this is due to the fact that Chelex�100 is an iminodiacetic acid meaning that two negative charges exist in very close proximity to one another, thus creating a local region of high electric field whereas the charge distribution within Bio-Rex�70 is uniform. This must play an important role in the selectivity of Chelex�100 for MCP transport and thereby increase the transference number of MCP.
When membranes are solvent cast from methylene chloride, the resin is added to the EVA/solvent mixture in wet (completely hydrated) form. When membranes are melt processed, the resin is first dried, then blended, melt pressed and finally the resultant film is rehydrated. We have found that the membranes obtained using these two processes have similar transport characteristics. We have also studied the effect of resin particle size and found that both Chelex�100 (100-200 mesh) and Chelex�100 (<400 mesh) exhibit an electrically-assisted steady state flux of about 300 μg/cm2 -hr. However, the larger particle size gives appreciably higher passive flux than the small particles. It is believed that this is because the large particles were of the same size as the thickness of the membrane and therefore a single particle could span the film providing a relatively large continuous pathway. For the smaller particles, several particles have to contact each other to provide a continuous pathway. These contacts were more than likely at small points and therefore appeared as restrictions and provided a more tortuous diffusion pathway thereby reducing the passive flux.
The relationship between steady state electrically-assisted transport, the JEK /JP ratio and the current density, was evaluated and found to be linear. This was established by testing an 18 volume percent Chelex�100 (<400 mesh)/EVA 40 composite membrane. The results obtained showed a linear relationship. Table II shows the range of measured resistivities and of the average measured flux values for MCP.
TABLE II______________________________________Current Density Resistivity FluxμA/cm2 kΩ-cm2 μg/cm2 -hr______________________________________50 1.4 73100 2.9 142200 3.6 276300 29.0 441417 2.4 644625 10.6 948______________________________________
Although this data has some fluctuations, four of the six resistivities measured were favorably less than the maximum desired or acceptable limit set at 10 kΩ-cm2 for use as a rate controlling membrane.
The magnitude of the passive transport is dependent on the volume fraction of resin within the membrane. However, the electrically-assisted transport is independent of this quantity. Therefore, the JEK /JP ratio can be predicted from the volume fraction of resin and other measurable quantities. This is illustrated in the following example.
Four hydrophilic resins were studied using an EVA 40 matrix: Chelex�100 (<400 mesh), Chelex�100 (100-200 mesh), Bio-Rex�70 and PVP-xl. Equation (11) was used to compare the JEK /JP ratios for various compositions of these composite membranes. The JEK /JP ratio for each composition was calculated versus the volume fraction (1/volume value) and the results are presented in FIG. 7. All membranes showed a linear relationship when plotted in this form. The ordinate of this plot originates at 1 because it is physically impossible to have volume fractions greater than 1, i.e., 1/H can never be less than 1. Only positive valued intercepts are meaningful in FIG. 7. A positive y-intercept indicates that a membrane made of pure ion exchange resin has some capacity to retard passive transport. The value of a positive x-intercept indicates at what resin loading the passive component of the flux greatly outweighs the electrokinetic transport. A resin that retards passive transport at high loadings is desirable. The slopes of the resulting linear regression best fit lines are presented in Table III. It is possible to compare the slopes directly because all experimental parameters (temperature, donor concentration, current density and membrane thickness) were identical in the determination of the JEK /P ratios plotted in FIG. 7. It is apparent that the small particle size Chelex�100 is the most selective for MCP.
TABLE III______________________________________Resin Slope______________________________________Chelex �100(<400 mesh) 28.5Chelex �100 (100-200 mesh) 4.03Bio-Rex �70 1.96PVP-x1 2.87______________________________________
The only anomaly in Table III is that it appears that the ability of membranes containing PVP-xl to control the passive flux of MCP is better than those containing Bio-Rex�70. It is true that Bio-Rex�70 is better at higher volume fractions, but the slope for PVP-xl is higher and therefore, at low volume fractions, the JEK /JP ratio is higher for PVP-xl membranes than for those containing Bio-Rex�70.
Having thus generally described our invention and described in detail certain preferred embodiments thereof, it will be readily apparent that various modifications to the invention may be made by workers skilled in the art without departing from the scope of this invention and which is limited only by the following claims.
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U.S. Classification | 604/20, 607/152 |
International Classification | A61N1/30 |
Cooperative Classification | A61N1/0444 |
European Classification | A61N1/04E1I2 |
Date | Code | Event | Description |
Mar 14, 1996 | FPAY | Fee payment | Year of fee payment: 4 |
Mar 14, 2000 | FPAY | Fee payment | Year of fee payment: 8 |
Mar 5, 2004 | FPAY | Fee payment | Year of fee payment: 12 |


text: Igarashi: Wii Ware Could Keep The 2D Dream AliveLeigh Alexander7/24/08 7:20pmFiled to: wii wareCastlevaniaIgarashi2D56EditPromoteShare to KinjaToggle Conversation toolsGo to permalinkDespite Castlevania's periodic forays into 3D games (many of which incite fanboy rage), series creator Koji Igarashi is long-known as a staunch supporter of the 2D aesthetic.AdvertisementAnd he tends not to keep his secrets too near his chest, readily expressing his interest in certain things (warming up to the Wii remote just prior to the revelation of Castlevania: Judgment, for example).So when Iga, asked by MTV Multiplayer about a return to classic Castlevania form on the console, expresses affinity for Wii Ware, it's easy to get fingers crossed for a traditional Castlevania on Wii:Advertisement"I'm definitely interested in WiiWare and I think it's one of the areas that 2D can still be very strong at," said Igarashi. "I'm very much looking into that."Hey, if Capcom can do it with Mega Man 9, we can dream, right?'Castlevania''s Igarashi Looking At WiiWare [MTV Multiplayer]Reply56 repliesLeave a reply

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Another Gay Sequel: Gays Gone Wild
Previously on Another Gay Movie, Todd Stephens's racist and pandering but almost canny response to American Pie, Nico thankfully lost his shit before almost getting it from Richard Hatch; Superman-ish Jarod gave in to Griff's big nerd cock; and Andy sacrificed his ass cherry to two dicks at once. Flash-forward to the equally desperate Another Gay Sequel: Gays Gone Wild, which begins with a nightmare that doesn't let up even after Nico (Jonah Blechman) wakes up. Virgins no more, the motley crew of fags (all played by different actors except for Blechman's nelly queen) travel to Fort Lauderdale—think Fire Island as reimagined by Rainbow Brite—for a fucktastic spring break that ends with trite lessons learned about monogamy, ostracism, and the sparring ways of the heart and hole. Having shot his satirical load on the first film, Stephens settles for grand-scale minstrelsy this time around, giving scant screen time to Lady Bunny and Whitney Houston—er, RuPaul—and way too much to Amanda Lepore's tits and our community's own Stepin Fetchit, Perez Hilton. Bigger, longer, and uncut—but only in the phallic sense—this mincing bad time is built entirely around shrill pop-culture references. But how queer am I for knowing that its only funny line was lifted whole from the great Romy and Michele's High School Reunion?
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Medium Zip-top Check Technical Pouch
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text:
Subject: | Alexi |
Author: | Siân (Authenticated as Sharley) |
Date: | June 3, 2010 at 12:38:24 AM |
I know the male name Alexi is a variant of Alexander, but where is the Alexi spelling most common?
I found a website that said it was Finnish, but I couldn't find anything to back that up.
Does anyone know?Thank you.
ETA: Pronounced something like ah-layk-chi.
ETA: Apparently, it's Greek. Thanks.
________________ "If we don't change our direction we're likely to end up where we're headed."
Chinese ProverbThis message was edited by the author on June 26, 2010 at 1:03:06 PM
Because this message is archived you cannot respond to it. |
Messages in this thread: |


text:
Fitzwater, DSN, RN
Associate Professor Emerita Associate Director of the College of Nursing University of Cincinnati |
Evelyn Fitzwater, DSN, RN, is Associate Director of the Center for Aging with Dignity. The Center is devoted to keeping people "SAFE After 60" by advocating for, advancing and developing best-practice programs on the safety and mistreatment of older adults. Recognizing that safety risks increase with age, we focus on enhancing the ability of professionals to empower older adults, families and organizations to maximize heath, wellness and independence. To learn more, please visit the Center for Aging with Dignity's website. Dr. Fitzwater graduated with her MSN from the University of Cincinnati in 1985 and received her DSN from the University of Alabama in 1995. She has been involved in the gerontology field for over 20 years, is a funded researcher with several published articles, and has served as an invited speaker and presenter for a variety of organizations on age-related topics. In 2005, Dr. Fitzwater was named Outstanding Leader in the Field of Aging by the Association for Professionals in Aging. |


text:
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Tangara: Blue lakes and emerald coasts
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We firmly believe that our tour leaders are some of the best out there – we've had tour leaders repeatedly nominated for the Wanderlust Guide of the Year award as well as one who has come away with the title a few years ago. In fact, we're always proud of the consistent praise they receive from clients, who tell us that not only do these inspiring tour leaders have an unbeatable blend of knowledge and people skills, they also know just how to uncover the hidden sides to all our destinations that make your trip unique.
Every year we receive hundreds of applications to become a Journey Latin America tour leader. Those successful are chosen based on a number of criteria and skills we feel will truly enhance your experience of Latin America:
We demand a lot from our tour leaders, but it is a job they are passionate about. So much so that many of our tour leaders have been with us for years (several over a decade) – and one, Etienne Frans, has been leading our tours for over a quarter of a century. They love what they do, and it shows in their performance and in the fantastic feedback we are proud to receive from our clients.
The latest figures speak for themselves:
What's more, in 2010, Pete Selman made it all the way to become Guide of the Year in the Wanderlust Guide of the year Awards, achieving first place out of a total of 1,500 global guide nominations sent in by clients. Since then Daniele Binaghi made the final in 2014 and has been shortlisted in 2015 and 2016.
But what means the most to us is that our clients consistently praise our hard-working tour leaders for their dedication, enthusiasm and insider knowledge, repeatedly attributing a large part of their enjoyment of the tour to their tour leader. Here are just a few of the things they had to say:
"We have travelled widely in Latin America with different companies, and enjoyed them all. But JLA's tour leaders have been particularly good, familiar with their adopted countries and culture and enthusiastic about their job." JF, Cambridge.
"The whole experience was memorable. A well-organised trip with lots of interesting things to see and do with people we got on well with and a knowlegeable, friendly, helpful guide." JR, Swansea
"Brilliant, amazing and so informative and well organised by our guide. Some wonderful memories, I would not hesitate to recommend it to a friend" AM, Newry
"I have done two trips with JLA and have found both to be an excellent experience. The tour leaders and the local guides have been superb and have made the holidays memorable and informative. I get the impression that tour leaders take their work very seriously and are committed to providing an excellent experience for their clients. Both trips I have done have been with small groups which I like very much." JG, Brentwood
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Caroline has a true love of travel, stemming from spending a month in Chile when she was just 16. Since then she has returned to Latin America many times, often indulging her love of adventure sports.
Food and Travel Magazine Readers' Awards - Tour Operator of The Year 2016
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text:
If it's springtime, that means that camping season is just days or weeks ahead. Prepper Mom, who writes at A Prepared Mother, submitted a list for my List Contest that I thought was too fun to not post. If you've ever gone long term camping, you'll be nodding your head in agreement, and then will have plenty more observations to add to this list!
- Snails can CEMENT themselves to nearly anything, and often they will do it in the least expected places.
- You MUST make peace with the giant spiders. They eat mosquitoes.
- Raccoons have no respect for personal property.
- If you fall asleep in in the open, don't be surprised if you wake up with wildlife curled up with you.
- Nothing shiny is ever safe in the open from raccoons.
- Armadillos like to lick plastic and exposed toes.
- Make peace with skunks or your life will stink (literally).
- Always look where you're taking a squat (answering nature's call) at least three times before going.
- Make sure you know what bull thistle looks like.
- Don't allow people to throw cigarettes in the latrines.
- Cedar smoke may be hard to live with, but mosquitoes are much harder to deal with.
- Don't camp by still waters.
- Clear well the area where you put your tent. Rocks, briars, and twigs don't just disappear because you put a tarp over them.
- Racoons will chew through things they cannot open easily.
- It's easier to appease the raccoon than to keep buying new things.
- Shake your clothes well before putting them on.
- Wet tobacco makes fire ant stings stop hurting.
- You may not react to the first, second or 100th fire ant bite, but someday you will and get huge welts from them.
- Don't camp anywhere near fire ants.
- No matter how awesome that spot in a valley looks, and no matter how much your significant other likes it, don't camp there. Water ALWAYS goes to the valley.
- Do not attempt to burn American literature books. It won't work.
- Raccoons can chew through sterilite containers.
- You cannot protect your valuables from raccoons unless you half bury a box in the ground and set a small boulder over it.
- Dont piss off Blue Jays. They remember and have no inhibitions in attacking you.
- ALWAYS, I repeat, ALWAYS check your shoes before putting them on.
What do you have to add?
There may be links in the post above that are "affiliate links." This means if you click on the link and purchase the item, I will receive an affiliate commission, which does not affect the price you pay for the product. Regardless, I only recommend products or services I use personally and believe will add value to my readers.
Latest posts by The Survival Mom (see all)
- 15 Survival Adventures Every Prepper Should Read - March 15, 2017
- Cold Weather Survival: Survive in a Stranded Car - February 22, 2017
- Do You Know How to Clean Up a Biological Mess? - February 6, 2017
- Top 10 Food Storage Myths - January 31, 2017
- Back to Basics Bundle: 70 Ebooks, Online Courses, and More! - January 17, 2017


text:
Entertainment for everyone
This is entertainment as it should be. Access a world of movies, TV and apps, and enjoy every moment in picture quality that goes beyond Full HD. All complemented by a rich, dynamic soundtrack.
This is entertainment as it should be. Access a world of movies, TV and apps, and enjoy every moment in picture quality that goes beyond Full HD. All complemented by a rich, dynamic soundtrack.
102 cm (40") KDL-40W650D | Rp. 5,788,421 |
121 cm (48") KDL-48W650D | Rp. 7,367,368 |
Experience stunning Full HD picture quality, whatever you're watching. Sony's unique X-Reality PRO processing engine analyses, cleans and refines images for beautifully detailed viewing. Even content streamed in low resolution is enhanced with X-Reality PRO to give a picture by Sony that brings everything you watch to life.
X-Reality PRO picture processing upscales every pixel for exceptional picture clarity. As frames are analysed, each scene is matched with our special image database to refine images and reduce noise – for a picture with incredible realism.
With a slim profile this TV blends seamlessly into your living space. It's perfect for wall mounting while its discreet, narrow bezel puts your focus firmly on the picture, not the frame.
Whether you want to rediscover a favourite movie, surf the web, or just check out a YouTube video, with a Sony TV the possibilities are endless.
Photo Sharing Plus is the easy way for you and your friends to share photos and videos on the big screen. Grab your favourites off the TV as friends share special memories — using up to 10 devices.
Screen mirroring lets you enjoy content and apps from your smartphone on your Sony TV. Supersize all your memories and enjoy them on the big screen with family and friends.
Play music, video clips and view photo collections all through your TV with super multi-format USB play. Supporting a wide range of codecs, you can experience ultimate format versatility, simply plug in and you're ready to go.
Sony is committed not only to offering products, services and content that deliver exciting experiences but also to working towards our goal of a zero environmental footprint throughout our business activities.
Read moreDynamic Backlight Control helps improve energy efficiency by adjusting backlight brightness as picture content changes.
Power Saving Mode helps save energy by adjusting backlight brightness.
Back Light Off Mode helps save energy by turning picture off which is realized by both display off on LCD panel and back-light off.


text: Sometimes two wrongs make a right. Sometimes three wrongs do. The latter is the case with the Famous Gerber. Wrong No. 1: Its main ingredient is Provel "cheese." Wrong No. 2: Served on French bread and topped with a melted portion of said "cheese" (the ham hides underneath), it's got this off-putting, uniform whiteness to it. Wrong No. 3: It is served in a sports bar by a woman wearing very revealing, hoping-for-a-job-at-Hooters clothing. So many wrongs, and yet...right on! Whether it's the sprinkle of paprika, the bread's satisfying crust, or -- could it be? -- the provel itself, a bewitching alchemy seemingly befalls DB's kitchen each time the Gerber is ordered. It's a gooey and greasy sandwich, surely, but an eye-rollingly delicious one as well. Finally, a reason for St. Louisans to take pride in Provel.


text:
The Four Noble Truths - Foreword
The Buddha's message is a universal one. We all search for happiness but somehow fail to find it because we are looking for it in the wrong way. Only when we start cherishing others will true happiness grow within us. And so the Buddha's essential teaching is one of compassion and ethics, combined with the wisdom that understands the nature of reality. The teachings of the Buddha contain everything needed to eliminate suffering and make life truly meaningful, and as such the teachings are not only relevant to today's world, but vital.
This is the message my precious teacher, Lama Thubten Yeshe, gave to his Western students. His vision to present the Dharma in a way that is accessible and relevant to everyone continues and grows. His organization, the Foundation for the Preservation of the Mahayana Tradition (FPMT), now has centers all over the world, and Lama's work is carried on by many of his students.
The Foundation of Buddhist Thought, developed by Geshe Tashi Tsering, is one of the core courses of the FPMT's integrated education program. The essence of Tibetan Buddhism can be found within its six subjects. The Foundation of Buddhist Thought serves as a wonderful basis for further study in Buddhism, as well as a tool to transform our everyday lives.
Geshe Tashi has been the resident teacher at Jamyang Buddhist Centre, London, since 1994. He has been very beneficial in guiding the students there and in many other centers where he teaches. Besides his profound knowledge—he is a Lharampa Geshe, the highest educational qualification within our tradition—his excellent English and his deep understanding of his Western students means that he can present the Dharma in a way that is both accessible and relevant. His wisdom, compassion, and humor are combined with a genuine gift as a teacher. You will see within the six books of the Foundation of Buddhist Thought series the same combination of profound understanding and heart advice that can guide beginner and experienced practitioners alike on the spiritual path.
Whether you read this book out of curiosity or as part of your spiritual journey, I sincerely hope that you find it beneficial and that it shows you a way to open your heart and develop your wisdom.
Lama Zopa Rinpoche
Spiritual Director
The Foundation for the Preservation of the Mahayana Tradition
How to cite this document:
© Geshe Tashi Tsering & Jamyang Buddhist Centre, The Four Noble Truths (Wisdom Publications, 2005)
This selection from The Four Noble Truths by Geshe Tashi Tsering is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License.
Based on a work at http://www.wisdompubs.org/book/four-noble-truths.
Permissions beyond the scope of this license may be available at http://www.wisdompubs.org/terms-use.


text: No recent wiki edits to this page. In Shin Megami TenseiDigital Devil Saga Mick the Slug transforms into the avatar Rahu when cornered by Serph and company at the top of Coordinate 136 after Cielo rescues Sera. During the battle, both his head and body are targetable and act independently. His body can use Dragon Quake, a powerful earth attack that hits your entire party, and his head can use Dragon Thrash to capture one of your party members. Party members captured in such a way will be drained of HP every time their turn comes up. They can only be freed by destroying either the head or the body, otherwise your captive party member will only be released when they are drained of HP completely. His head will still fight on if you destroy the body, and vice versa.Digital Devil Saga 2 Mick the Slug's "data" is encountered near the end of the game, and challenges you again as Rahu. He fights exactly the same as he did in Digital Devil Saga, only he has more HP.


text:
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Why do an SD Card Mod?
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DD-WRT Novice
Joined: 24 Feb 2011
Posts: 5
Posted: Thu Feb 24, 2011 21:21
Post subject: Why do an SD Card Mod?
So, the subject line is pretty self-explanatory. I've looked all over the forum, and Google, and can only seem to find how-to's and not come up with a reason WHY to do any of these mods. I'm a major geek myself, and planned on doing a mod just to add a fan/heatsink to aid in cooling when I jack up the signal, and wanted to look into other stuff.
It seems that I can't increase my flash capability (say, for using MEGA on a WRT54G) by adding an SD card, but what capability would adding an SD card port give me? I'm guessing being able to run programs and such from the router, but how's about a few general ideas? I'm (very) new to programming and coding, so compiling my own code (for now) is out of the question, but being pointed in the right direction to do new cool stuff would be nice.
Thanks all for the newbie patience, it's much more appreciated than you could ever know.
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DD-WRT User
Joined: 16 Feb 2011
Posts: 51
Posted: Fri Feb 25, 2011 2:27
Post subject:
Another guess would be sparing the routers flash over use with stuff that stores data on the remaining flash with JFFS. Mind you id rather have something over a particular size its probably still useful for something.
My router has 32mb of flash and uses less than 8 for a build so if someone wasnt worried about killing it DDWRT, tomato and other firmware/mods allow for utilizing the extra flash for jffs. Its just inadvisable to use it for something thats doing alot more writing than just reading.
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DD-WRT Novice
Joined: 24 Feb 2011
Posts: 5
Posted: Fri Feb 25, 2011 15:17
Post subject: JFFS info
After reading your post, I looked up what JFFS was, and from what I can tell, it's a file transfer protocol that allows the use of USB and stuff, and what I'm finding is that JFFS has a major conflict with VPN, and has for the most part been removed from DD-WRT. I'm sure that there's plenty of use for JFFS, but even a basic explanation of it would help.
Anyone got any other ideas? I've got no idea what the different services are, and reading the Wiki only goes so far.
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DD-WRT User
Joined: 16 Feb 2011
Posts: 51
Posted: Fri Feb 25, 2011 22:20
Post subject:
JFFS is a file system for flash memory. It can be utilized for a number of tasks by a number of addons and features. The point being alot of use of left over router flash will wear it out. NOR flash while cheaper has less life expectancy. Anything you might wish to use to store data on the router flash would be better off done with an sd card. What those would be is of course your question that i cant answer. But thats a reason for adding on small flash sd cards.
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DD-WRT Novice
Joined: 24 Feb 2011
Posts: 5
Posted: Sat Feb 26, 2011 21:07
Post subject:
Seems like there's plenty of reasons to add an SD card, but I'm just looking for a generalized list of things that I could do; add programs to run. But, how's about a few ideas of WHAT programs to run? I have no idea what I want to do, because I honestly don't know what I CAN do. Anyone?
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DD-WRT Novice
Joined: 24 Feb 2011
Posts: 5
Posted: Sun Mar 06, 2011 22:36
Post subject:
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DD-WRT Novice
Joined: 18 Aug 2008
Posts: 19
Posted: Tue Mar 08, 2011 20:14
Post subject:
bump X2
I'm also interested about such kind of improvements.
if it can't run a bigger firmware (ex: mega) then what's is it usefull for?
I would like some clear example of what it can do more please.
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DD-WRT User
Joined: 07 Feb 2009
Posts: 198
Posted: Mon May 09, 2011 15:39
Post subject:
To store more stuff in your router.
Sometimes flash/nvram is too small for complex firewall rules, QOS, scripts, VPN certificates, large dns host file, pixel-serv ad-blocking, etc, etc...
If you don't know WHY is probably because you have not reached the limit of your router flash.
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DD-WRT Novice
Joined: 17 Apr 2011
Posts: 7
Posted: Wed May 11, 2011 17:29
Post subject:
well, for starters, you could install a much more robust linux variant while using the flash space for the base kernel and core boot loaders.
some other ideas:
- install a packet sniffer allowing you to use your router to test network security.
- run a DB server and store the database directly on the device instead of having it point to a network location
- install and run apache and have the web pages on the device instead of having to use NFS
- on some routers, the SoC even contain a PCI bridge meaning if you could figure out how to mod in a pci slot you could add various functionalities while storing the needed drivers/software on the SD card (some also have IDE capability!)
- use it as wirelessly attached network storage (even better with a USB mod though)
- run a POP/IMAP mail server directly off the router and store mail, access lists, and virus scanners
- use it as a login server for your entire network (Open Directory Master)
- run a streaming server relay
- run a headless x-windows VNC server with any flavor of window manager you can think of
- run a coding slave
- run a system update cloud
since ddwrt is basically a very small linux variant, you can add any of these features and more by using a pkg manager of your choosing and installing the required dependencies. essentially, the more memory you add to the machine, the possibilities become endless
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DD-WRT Novice
Joined: 28 Aug 2011
Posts: 3
Posted: Sun Aug 28, 2011 18:56
Post subject: A lightweight X11 on a WZR-HP-G300NH router?
I have a WZR-HP-G300NH router and I want to make it more interactive by getting Xwindows to run remotely from it. I don't know how to do this.
Has any one had any experience getting Xwindows running remotely from a wireless router
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DD-WRT Novice
Joined: 28 Aug 2011
Posts: 3
Posted: Thu Sep 22, 2011 12:41
Post subject: X-windows VNC server
-run a headless x-windows VNC server with any flavor of window manager you can think of...
I am interested in running this on a WZR-HP-G300NH router.
Please how can I do this?
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Items where Person is "Amat, A"
Group by: Item Type | No Grouping Number of items: 1. Amat, A and Burgeot, T and Castegnaro, Marcel and Pfohl-Leszkowicz, Annie DNA adducts in fish following an oil spill exposure. (2006) Environmental Chemistry Letters, vol. 4 (n° 2). pp. 93-99. ISSN 1610-3661 |


text:
Human Capital Management Institute's (HCMI) Workforce ROI Calculator™ is the first-ever quick and easy to use advanced analytics tool that quantifies the financial impact of workforce interventions. Users have the ability to forecast cost savings and value creation scenarios for the entire organization, entity, or business unit, and for specific position groups or critical job roles. The calculator was created as a simple template to generate the maximum amount of value creation, financial cost, and HR ROI information from the fewest possible data inputs.
The purpose of the Workforce ROI Calculator™ is to provide HR and Finance professionals a straightforward tool to analyze and predict workforce cost and value implications. Specific areas of analysis include workforce productivity, engagement, performance, retention, mobility and training, among others.
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Why use this calculator? Finance organizations have been using standard net present value (NPV), return on investment (ROI), and internal rate of return (IRR) templates and calculation models for decades; yet no such calculator has existed until now to quantify or support data driven decision making for the workforce.
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