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Membrane for electrotransport transdermal drug delivery
A membrane capable of inhibiting agent release from a delivery system when no electrical current is flowing and yet provide minimal impedance to electrically-assisted agent delivery, useful both for incorporating into electrotransport agent delivery systems and for use in measuring agent release rates in in vitro testing.
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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.BACKGROUND OF THE INVENTION
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, .gradient..PHI..
J.sub.i =-[D.sub.i .gradient.C.sub.i ]-[z.sub.i F u.sub.i C.sub.i .gradient..PHI.]+[C.sub.i v] (1)
J.sub.i =flux of species i (moles/cm.sup.2 -sec)
D.sub.i =diffusion coefficient of i (cm.sup.2 /sec)
.gradient.=the gradient operator
C.sub.i =concentration of i
z.sub.i =number of charges per molecule of i
F=Faraday's constant (96,500 coulombs/mole of charge)
u.sub.i =mobility of i (velocity/force=sec/g)
.PHI.=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:
J.sub.i,x =-[(D.sub.i) (dC.sub.i /dx)]+[z.sub.i F u.sub.i C.sub.i E.sub.x ]+[C.sub.i v.sub.x ] (2)
J.sub.i,x =the total electrically-assisted flux of species i in the x direction
E.sub.x =-(d.PHI./dx)=the electrical field in the x direction i.e. the negative of the electrical potential gradient
v.sub.x 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 D.sub.i, c.sub.i, u.sub.i, 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, t.sub.i, which is the fraction of current carried by species i, the electromigration flux of species i, J.sub.i,EM, may be expressed as the product of the transference number and the current density passing through the medium:
J.sub.i,EM =[(t.sub.i) (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, J.sub.i,EO, is related to the total current passing through the membrane by the following equation:
J.sub.i,EO =(.epsilon..zeta.I)/(.kappa..degree..mu.A) (4)
.epsilon.=the dielectric constant of the liquid medium
.zeta.=the zeta potential of the membrane having a fixed charge
.kappa..degree.=the conductivity of the liquid phase
.mu.=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, J.sub.EK.
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, J.sub.p. The sum of all three terms in equation (2) will be called the electrically-assisted flux, J.sub.EA :
J.sub.EA =J.sub.P +J.sub.EM +J.sub.EO ( 5)
Since the electrokinetic flux, J.sub.EK, is the sum of the flux due to electromigration and the flux due to electroosmosis, equation (5) can be simplified to:
J.sub.EA =J.sub.P +J.sub.EK ( 6)
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 .mu.A/cm.sup.2 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.RTM. 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.SUMMARY OF THE INVENTION
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.BRIEF DESCRIPTION OF THE DRAWING
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 J.sub.EK /J.sub.P ratio of metoclopramide through various membrane compositions of this invention.DESCRIPTION OF THE 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 J.sub.EK /J.sub.P 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 J.sub.EK /J.sub.P 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 J.sub.RP and J.sub.MP, 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, J.sub.P, is given by:
J.sub.P =[(H) (J.sub.RP)]+[(1-H) (J.sub.MP)] (7)
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, J.sub.EK, i.e., there is no ionic conduction or electroosmotic flow through the hydrophobic matrix material. Therefore, the electrokinetic flux may be written as:
J.sub.EK =([(t.sub.D) (I)]/A)+[(.epsilon..zeta.I)/(.kappa..degree..mu.A)](8)
where t.sub.D 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 J.sub.MP 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, J.sub.RP, may be written as:
J.sub.RP =[(D) (C.sub.D)]/1 (10)
D=the diffusion coefficient of the drug through the resin
C.sub.D =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:
J.sub.EK /J.sub.P =(t.sub.D I l)/(H D C.sub.D A) (11)
This simplified form indicates that J.sub.EK /J.sub.P is inversely proportional to the volume fraction of resin, and therefore, the J.sub.EK /J.sub.P ratio should increase as the resin loading is decreased. From equation (11), it also can be predicted that thicker membranes should exhibit a larger J.sub.EK /J.sub.P 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 J.sub.EK /J.sub.P 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, t.sub.D, also depends on the drug concentration, but it is not a linear dependence. For large transference numbers, t.sub.D is nearly independent of concentration. However, for small transference numbers, t.sub.D is linearly dependent on donor concentration. Therefore, reducing the donor drug concentration will only increase the J.sub.EK /J.sub.P 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 J.sub.EK /J.sub.P 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 .mu.A/cm.sup.2, i.e., the membrane resistivity should be less than 10 k.OMEGA.-cm.sup.2.
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.RTM., 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 Resins AG 50W-X12* H 100-200 5 2.3 42-48 small (Sulfonic acid) Bio-Rex .RTM.70* Na 200-400 10.2 3.3 65-74 large (Carboxylic acid) Chelex .RTM.100* Na 100-200 2.9 0.7 71-76 large Chelating resin (Iminodiacetic acid) Amberlite H 20-50 5.0 1.8 49-55 medium IR-120** (Sulfonic acid) Anion Exchange Resins AG 1-X8* Cl 20-50 3.2 1.4 39-45 medium (R.sub.4 N.sup.+) Amberlite Cl 20-50 3.3 1.2 42-48 medium IRA-400** (RN(CH.sub.3).sub.3.sup.+) __________________________________________________________________________ *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 cm.sup.2 to greater than 200 cm.sup.2. The average system however, has a size within the range of about 5-50 cm.sup.2. 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.EXAMPLE I
Commercially available polypropylene and polyethylene based microporous membranes (Cellgard.RTM. manufactured by Celanese), polycarbonate and polyester microporous membranes (Nuclepore.RTM.), cellulose and cellulose acetate membranes with varying amounts of triacetin and a porous glass material (Vycor.RTM., Corning No. 7930) were cut to the appropriate size and used as supplied. Pore sizes ranged from 40 .ANG. for the porous Vycor.RTM. to 0.2 .mu.m for Cellgard.RTM. 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.degree. C. Cells operating under passive conditions had zero current applied while cells operating under active or electrically-assisted conditions had 100 .mu.A/cm.sup.2 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.RTM. 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.EXAMPLE II
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.RTM., Raipore 1010, Raipore 4010 and Raipore 5010. Nafion.RTM. 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.EXAMPLE III
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.RTM.70, a macroreticular acrylic polymer based carboxylic acid cation exchange resin made by Bio-Rad Laboratories, and Chelex.RTM.100, a styrene divinylbenzene lattice with paired iminodiacetate cation exchange groups also made by Bio-Rad Laboratories. Two particle sizes of Chelex.RTM.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.RTM.70 and Chelex.RTM.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.RTM.70 were solvent cast from methylene chloride and dried at ambient conditions. Both methods of preparation were used for membranes containing Chelex.RTM.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.RTM.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 J.sub.EK /J.sub.P ratios for several of the membranes tested. The data represents the average steady state flux values.
TABLE I ______________________________________ Polymer Resin Resin Loading, vol % J.sub.EK /J.sub.P Ratio ______________________________________ EVA 40 Bio-Rex .RTM.70 17.4 6 22.9 2.5 33.8 1 EVA 28 PVP-x1 12 6.4 18 0.9 25 0.4 34 0.3 EVA 40 Chelex .RTM.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 J.sub.EK /J.sub.P 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.RTM.100 exhibited larger J.sub.EK /J.sub.P ratios than Bio-Rex.RTM.70, which in turn was better than PVP-xl. Both Chelex.RTM.100 and Bio-Rex.RTM.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 J.sub.EK /J.sub.P ratio in Chelex.RTM.100 and Bio-Rex.RTM.70 membranes. Interestingly, Bio-Rex.RTM.70 has a higher fixed charge density than Chelex.RTM.100, yet it exhibited lower J.sub.EK /J.sub.P ratios. We believe that this is due to the fact that Chelex.RTM.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.RTM.70 is uniform. This must play an important role in the selectivity of Chelex.RTM.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.RTM.100 (100-200 mesh) and Chelex.RTM.100 (<400 mesh) exhibit an electrically-assisted steady state flux of about 300 .mu.g/cm.sup.2 -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.EXAMPLE IV
The relationship between steady state electrically-assisted transport, the J.sub.EK /J.sub.P ratio and the current density, was evaluated and found to be linear. This was established by testing an 18 volume percent Chelex.RTM.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 Flux .mu.A/cm.sup.2 k.OMEGA.-cm.sup.2 .mu.g/cm.sup.2 -hr ______________________________________ 50 1.4 73 100 2.9 142 200 3.6 276 300 29.0 441 417 2.4 644 625 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 k.OMEGA.-cm.sup.2 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 J.sub.EK /J.sub.P ratio can be predicted from the volume fraction of resin and other measurable quantities. This is illustrated in the following example.EXAMPLE V
Four hydrophilic resins were studied using an EVA 40 matrix: Chelex.RTM.100 (<400 mesh), Chelex.RTM.100 (100-200 mesh), Bio-Rex.RTM.70 and PVP-xl. Equation (11) was used to compare the J.sub.EK /J.sub.P ratios for various compositions of these composite membranes. The J.sub.EK /J.sub.P 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 J.sub.EK /.sub.P ratios plotted in FIG. 7. It is apparent that the small particle size Chelex.RTM.100 is the most selective for MCP.
TABLE III ______________________________________ Resin Slope ______________________________________ Chelex .RTM.100(<400 mesh) 28.5 Chelex .RTM.100 (100-200 mesh) 4.03 Bio-Rex .RTM.70 1.96 PVP-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.RTM.70. It is true that Bio-Rex.RTM.70 is better at higher volume fractions, but the slope for PVP-xl is higher and therefore, at low volume fractions, the J.sub.EK /J.sub.P ratio is higher for PVP-xl membranes than for those containing Bio-Rex.RTM.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.
1. A membrane for controlling agent delivery from an electrotransport delivery system, the membrane permitting electrically-assisted flux (J.sub.EK) of the agent therethrough and impeding passive flux (Jp) of said agent therethrough, the membrane exhibiting a ratio of J.sub.EK:J.sub.P of at least about 2.5.
2. The membrane of claim 1 wherein said membrane is comprised of a hydrophilic resin blended into a hydrophobic polymeric matrix.
3. The membrane of claim 2 wherein said hydrophilic resin is cross-linked polyvinylpyrrolidone.
4. The membrane of claim 2 wherein said hydrophilic resin is an ion exchange resin.
5. The membrane of claim 4 wherein said ion exchange resin has a functional group selected from the group consisting of sulfonic acid, carboxylic acid, iminodiacetic acid and quaternary amines.
6. The membrane of claim 2 wherein said hydrophilic polymer matrix comprises an ethylene vinyl acetate copolymer having a vinyl acetate content of about 1 to 40 wt. %.
7. The membrane of claim 2, wherein the hydrophilic resin has a high permeability for said agent and the hydrophobic polymer matrix has a low permeability for said agent.
8. The membrane of claim 2, wherein the hydrophilic resin comprises less than about 15 vol. % of the membrane.
9. The membrane of claim 4, wherein the ion exchange resin is a macroreticular acrylic polymer based carboxylic acid cation exchange resin and the resin comprises less than about 23 vol. % of the membrane.
10. The membrane of claim 4, wherein the ion exchange resin comprises a styrene divinylbenzene latice with paired iminodiacetate cation exchange groups.
11. The membrane of claim 10, wherein the resin comprises up to about 50 vol. % of the membrane.
12. The membrane of claim 1 wherein said membrane is positioned between a reservoir containing the agent and said body surface.
13. The membrane of claim 1 wherein said membrane is positioned between an agent reservoir and said body surface, said agent reservoir being positioned between an electrolyte reservoir and said membrane.
14. The membrane of claim 1, wherein the membrane exhibits a resistivity of less than about 10 kohm-cm.sup.2.
15. An electrotransport agent delivery system for placement on a body surface comprising:
- a backing member;
- a source of electrical power;
- first and second current conducting members electrically connected to the source of electrical power;
- reservoir means containing an agent to be delivered, said reservoir means being electrically connected to one of said first and second current conducting members;
- 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, whereby said means for controlling agent delivery permits electrically-assisted flux (J.sub.EK) of the agent therethrough and impedes passive flux (J.sub.P) of the agent therethrough, the means for controlling agent delivery also exhibiting a ratio of J.sub.EK:J.sub.P of at least about 2.5.
16. The system of claim 15 wherein said means for controlling agent delivery is a membrane comprised of a hydrophilic resin blended into a hydrophobic polymeric matrix.
17. The system of claim 16 wherein said hydrophilic resin has a high permeability for said agent and said hydrophobic polymeric matrix has a low permeability for said agent.
18. The system of claim 17 wherein said hydrophilic resin is cross-linked polyvinylpyrrolidone.
19. The system of claim 17 wherein said hydrophilic resin is an ion exchange resin.
20. The system of claim 19 wherein said ion exchange resin has a functional group selected from the group consisting of sulfonic acid, carboxylic acid, iminodiacetic acid and quaternary amines.
21. The system of claim 17 wherein said hydrophobic polymer matrix comprises an ethylene vinyl acetate copolymer having a vinyl acetate content of about 1 to 40 wt. %.
22. The system of claim 15 wherein said agent is a macromolecule.
23. The system of claim 22 wherein said agent is selected from the group consisting of peptides, polypeptides and proteins.
24. The system of claim 15 wherein said agent is selected from the group consisting of metoclopramide, baclofen, betamethason, beclomethasone, doxazosin, droperidol, fentanyl, sufentanil, leuprolide, lidocaine, methotrexate, micanazole, prozosin, piroxicam, verapamil, tetracaine, diltiazam, indomethacin, hydrocortisone, terbutaline and encainide.
|March 1974
|March 13, 1979
|June 23, 1981
|April 20, 1982
|July 5, 1983
|Cahalan et al.
|December 6, 1983
|Jacobsen et al.
|July 3, 1984
|Lattin et al.
|October 2, 1984
|Ariura et al.
|December 10, 1985
|November 11, 1986
|February 3, 1987
|June 16, 1987
|DiLuccio et al.
|August 25, 1987
|October 27, 1987
|Powers et al.
|November 24, 1987
|December 15, 1987
|February 2, 1988
|Sanderson et al.
|March 15, 1988
|March 22, 1988
|June 27, 1989
|Konno et al.
|February 27, 1990
|Therrinoh et al.
|July 10, 1990
|Sibalis et al.
|January 14, 1992
|Theeuwes et al.
- P. Tyle & B. Kari, "Iontophoretic Devices," in Drug Delivery Devices, pp. 421-454 (1988).
Type: Grant
Filed: Aug 28, 1991
Date of Patent: Sep 15, 1992
Assignee: Alza Corporation (Palo Alto, CA)
Inventors: Felix Theeuwes (Los Altos, CA), J. Richard Gyory (Los Altos, CA), Ronald P. Haak (Cupertino, CA)
Primary Examiner: Stephen C. Pellegrino
Assistant Examiner: Michael Rafa
Attorneys: D. Byron Miller, Edward L. Mandell, Steven F. Stone
Application Number: 7/751,276
International Classification: A61N 130;


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Science Fiction Writer Tony Thorne Beams Down for a Visit with Mike Angley
MA: I am delighted to have as my guest-blogger today, Tony Thorne. Tony is an Englishman, born and technically educated in London, England, and now living in Austria; but in the winter, he lives in the warmer Canary Island of Tenerife. He originally qualified as a Chartered Design Engineer and subsequently created a well-known British company specializing in Applied Physics products. For developments in the field of low temperature (cryo)surgery instruments, and very high temperature (carbon fibre) processing furnaces, the Queen awarded Mr. Thorne an MBE.
Well, that's quite a scientific and technical background. I would have guessed you'd write technical books, textbooks, or articles for scientific journals. Why fiction?
TT: Much earlier in life I wrote and sold some science-fiction and humorous stories, was an active SF Fan, and a spare time lecturer for the British Interplanetary Society. After many business adventures, including the development of AI computer software for business applications, and animated computer graphics set to music, I now write quirky speculative yarns; mostly Science Fiction and Macabre tales, with a novel and over 100 short stories on file. Most of the latter are available in different collections.
I'm really a short story writer but Harry Harrison said I should write a novel if I want to be really successful … so I've recently completed one. Incidentally, Harry wrote the introduction to my Tenerife Tall Tales SF collections.
Most of my quirky SF and Macabre Tales are set in, on and even under, that magical Canary Island of Tenerife, where I spend every winter. Apart from those, I like to scan the science news for the latest developments and then write a tall tale about the possible consequences.
MA: So, tell us how you blend your science and technical background into your novel.
TT: In my novel, POINTS OF VIEW, the hero is a young blind boy, named Horace Mayberry, who gets fitted out with some nanotronic eyes. They are intelligent and can develop various functions to suit whatever scrapes the lad gets into. He is recruited into a secret government agency as an assistant to an experienced agent and embarks on a series of adventures, including being abducted twice by an international gang of crooks. Each situation causes his eyes to develop something new, and enables his introvert personality to evolve, too.
The finale covers an attack on the crooks hideout in Tenerife … where else! I had a lot of fun writing it.
MA: I love fiction that embraces technology like this. Tell us about your hero and villain.
TT: Horace is a cautious lad, very introvert initially. Then as his abilities develop he becomes impulsive and somewhat headstrong. The main crook, Rudolph Beckman, is an international billionaire financier who is after the secret of the company that developed the nanotronic eyes. He uses a trio of henchmen to do his bidding.
MA: Now, I'm sure your real-world exposure to emerging technologies influenced the plot in Point of View, but was that all? Did any other life experiences factor into the story?
TT: That's a very interesting question. Yes, part of Horace's training mirror's some of my experiences when I joined the army, so many years ago.
MA: So what's next in your fiction future?
TT: I'm currently working on a couple of new short stories and also finalizing a collection of quirky short tales and some poems which are to be published in the USA next year, entitled INSIDE INFORMATION. They're items I've performed in costume, at SF Conventions and various other events.
I am also thinking about a sequel to the novel … there's plenty of scope in the idea. Other than that, some of my short Tenerife tales feature common characters, and will continue to do so.
MA: I know your love of science drives you, but what else?
TT: It can't be for the money, but more of that would be nice … I guess it's really an insatiable craving to be recognized.
MA: (Chuckling). Thanks, Tony, for being my guest today. I encourage my readers to visit Tony's website for more information about this intriguing author: www.tonythorne.com. Read More

subset: commoncrawl


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LIGHT AND WATER: The sights and sprays of Yosemite Valley are some of the best-known in the world, and especially in the springtime, when the national park's waterfalls are at their most robust. But it isn't always just the water-and-rock element that visitors journey to the Sierra to see. Very often how the light plays off the famous falls is the draw, specifically at certain times of the year or certain phases of the moon. Take the Horsetail Fall's annual "firefall," a mid-February marvel that results from the rays of a setting sun and the fall itself (the "fire" in the name is a clue as to the appearance). But moonbows can also be seen around the valley at certain times. Surely you know the moonbow, yes? Less common than a rainbow but just as magical, a moonbow is simply a bow created from light reflected from our lunar orb. We'd almost be inclined to call them even more magical than rainbows, since the light has to make a pit stop on the moon before reach our watery planet, but we don't want to be accused of thinking anything is more magical than a rainbow. That's practically law, right?
HERE COMES A MOONBOW NOW: There may be a chance to see this enchanted sight on the evening of Saturday, May 25 at Lower Yosemite Fall. "May" is the operative word, of course. As with all natural wonders and marvels, timing, atmosphere, and a hundred other elements play into the final result. But, still, there's a full moon due, and there are only "a few days a year," per a Yosemite site, that a bow is possible. May 25 is one, hooray hooray, so bet the bow buffs'll be out. Even if the magic doesn't happen, you'll be in the Valley, on Memorial Day Weekend, so we're just betting you'll find a horse to ride or a hike to join.
MOONBOW PREDICTIONS: The moonbow predictions shared by Yosemite are made by Texas State University researchers. Wouldn't you love to be a moonbow predictor? No joshing here. We'd put that at the top of our resume, out of pure pride.


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Practicing employment law can be very complex yet very fulfilling. It can involve employment discrimination suits, which range from race, sex, age or disability discrimation to cases which pertain to misappropriation of trade secrets or suits to enforce Non-Competition Agreements. You might represent the employee who feels wronged, or you could represent employers against those claims. If you defend the employers part of your responsibility would be to advise the employers how to best avoid these suits.
These cases typically involve complicated relationships between people in the workplace and therefore may be fraught with emotion and hurt feelings. There is a very human component to this field, so a prerequisite needed to practice in this field would be people skills. You must develop a real trust relationship with your clients and serve as their competent advisor, regardless of the side you argue. You should also possess excellent writing skills and ensure that you are up to date on the latest developments in the field.


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Wednesday, December 1, 2010
A Basket of 'Googies'
Little Red Riding Hood lives at my house. No matter where you are - she'll find you, with her basket of 'googies' in tow. An imaginary wolf hides behind the couch, or under the dining table - always ready to leap out and frighten our little heroine away. But she persists. She's very stubborn, our Little Red.
9 comments:
I once had a roommate mistake curry powder for cinnamon and it made excellent oatmeal cookies. It's crazy how the "savory" spices can really work in sweets sometimes, no?
- December 2, 2010 at 7:29 AM
- Easy peasy organic said... [Reply to comment]
How funny! Do you have the recipe? I wouldn't mind trying curried oatmeal cookies!
- December 2, 2010 at 5:17 PM
Dear Amanda,
My name is Cacau (in portuguese is the same as cocoa) and I am from Brazil. I found your blog browsing around ... And in a matter of 2 days I read almost every posts you have published! Fantastic, amazing, and very very inspiring.
You are one of a kind :)
I wish you all the best :)
- December 3, 2010 at 2:26 PM
- Easy peasy organic said... [Reply to comment]
Cacau - lovely to meet you! Thanks for sending the note ... it means a lot to me to hear that you've been inspired :)
We love Brazil, and hope to get back there soon - a few years ago my husband and I did some work in Sao Paolo and then had a holiday in Paraty. We ate way too much and drank way too many caproskas.
And loved every minute!
- December 3, 2010 at 3:42 PM
- T. Martin said... [Reply to comment]
What do you mean by raw sugar? Granulated sugar?
- December 8, 2010 at 12:41 AM
- Easy peasy organic said... [Reply to comment]
@T. Martin
It's less processed than regular sugar - there's more information and a link to even *more* information on my What Is page at http://www.easypeasyorganic.com/p/what-is.html
Hope this helps!
- December 8, 2010 at 4:36 AM
These cookies sound delicious!!I like the savory and sweet!!
- December 8, 2010 at 10:28 AM
Can these be made w/ out the egg? Any tips?
- July 26, 2013 at 12:02 PM
- Easy peasy organic said... [Reply to comment]
@Anonymous You could try 1/4 cup applesauce ... I haven't done so, but it seems to be a generally-used egg substitute in baking. Good luck! Axx
- July 26, 2013 at 9:51 PM


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Hara and Sonic 540 Mach 2 Win 2013 TITC!
Atsushi Hara continues to be one of the fastest RC racers on the planet. At the 2013 TITC at the R/C Addict Circuit in Bangkok, Thailand, Hara put on an impressive driving display at one of the world's most challenging circuits.
Equipped with a new Sonic 540 Mach 2, Hara conquered the track, the high heat, and humidity, as well as a field of world-class competitors to top the time sheets in qualifying. After a bad start in A1, Hara came back with a vengeance to win A2 and A3 in convincing fashion and take the overall title.
Congratulations to Atsushi and all the competitors, with special thanks to the organizers for hosting this incredible event.
Products used:
#244 Reedy Sonic 540 Mach 2 4.5


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International travel to the United States generates $165.5 billion in revenue and supports 1.1 million American jobs, making travel the nation's top service export. Despite a booming global travel market, however, the U.S. market share has seriously lagged because of chronic inefficiencies in our visa and entry process.
The Discover America Partnership (DAP) is a diverse coalition of industries and associations whose work depends on safe and efficient inbound international travel. The core missions of DAP members vary from petroleum engineering to river cruises, from entomology to martial arts and consumer electronics. The common thread is the need for overseas colleagues and customers to be able to reliably visit the U.S. for professional conferences, trade shows, business negotiations as well as for tourism.
Too often, delay and confusion in our entry process discourage legitimate visitors–and the revenue and jobs their spending generates. The DAP seeks to solve these problems, without in any way undermining security.
California Chamber of Commerce is a nonprofit organization committed to helping California businesses survive and thrive while complying with complex laws and regulations. Their more than 13,000 members are a diverse group, ranging from companies such as Microsoft and the Walt Disney Corporation to local companies with only a handful of employees.
The Visa Waiver Program (VWP) is one of the most important national security and public diplomacy tools available to the US. It's also an economic dynamo, generating American jobs - as shown by the significant impact of South Korea's inclusion within the VWP.
Read More
The Discover America Partnership has a broad Washington, D.C. agenda aimed at enhancing the safety and efficiency of the United States visa and entry process. Here's an overview of where things stand now.


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Trans advocates Sarah McBride and Prof. Jennifer Finney Boylan discuss McBride's powerful new memoir, "Tomorrow Will Be Different."
Before Sarah McBride became the first transgender person to speak at a national political convention, Sarah struggled with the sadly familiar challenge several young members of the LGBTQ community face: whether or not to come out – not just to family, but to her peers, her classmates she led from her role as student body president.
Sarah knew she was a girl from her earliest memories, but it wasn't until the Facebook post announcing her truth went viral that she realized just how much impact her story could have on the country. Four years later, she had become one of the most prominent transgender activists, working within the walls of the White House, advocating the passing of laws, and addressing the country in the midst of a heated presidential election.
Informative, heartbreaking, and empowering, "Tomorrow Will Be Different" is Sarah's story of love and loss, a powerful entry into the LGBTQ community's battle for equal rights and what it means to be openly transgender.
Sarah McBride is a LGBT rights activist and political figure. She is currently the National Press Secretary of the Human Rights Campaign, and is largely credited with the passage of legislation in Delaware banning discrimination on the basis of gender identity in employment, housing, insurance, and public accommodations. She has been a speaker at the Democratic National Convention, becoming the first openly transgender person to address a major party convention in American history.
Professor Jennifer Finney Boylan, author of fifteen books, is the inaugural Anna Quindlen Writer in Residence at Barnard College of Columbia University. Her column "Men & Women" appears on the op/ed page of the New York Times on alternate Wednesdays. From 2011 to 2018 she served on the Board of Directors of GLAAD, the media advocacy group for LGBT people worldwide. She was a consultant and cast member for I AM CAIT, the docu-series about Caitlyn Jenner that debuted on the E! network in July of 2015; and also served as a consultant to the Amazon series TRANSPARENT. Her 2003 memoir, "She's Not There: a Life in Two Genders" (Broadway/Doubleday/Random House) was the first bestselling work by a transgender American.


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A Big Vision
Think Big. It's one of those phrases you probably hear so much that you don't really take a moment to consider the words. What would happen if we all took a minute to focus? To truly THINK and ponder our goals, our future and what we are willing to do to make those things a reality. Now, imagine what each of us could achieve if we consider our short-term goals and achievements as part stepping stones to the big things.
For you, that might mean becoming an Eagle, it might mean more financial stability or doing Forever full time, taking your family on an epic vacation or earning a Chairman's Bonus check. For me, THINKING BIG means doubling our business and helping more people all over the world look better and feel better.
Those of you who joined us in Dubai saw the embodiment of where "thinking big" can get you. Just a few decades ago, Dubai was little more than a desert town. Many suggested that it could never be anything but. However, his Highness Sheikh Mohammed bin Rashid Al Maktoum, the ruler of Dubai, wasn't deterred. He recognized that the only thing missing was a clear vision for the future and a steadfast belief that Dubai could be one of the most magnificent cities in the world.
In his words, the UAE is "the embodiment of confronting difficulties, overcoming obstacles and conquering the impossible". When Dubai envisioned the Burj Khalifa 15 years ago, do you think that they wanted a "nice" building? Of course not! They wanted THE biggest, THE best, the most INCREDIBLE tower the world had ever seen!
Their vision was beyond what was tangible in the moment. Had they set their sights lower, there's no doubt that they could've built that tower – but instead they chose to THINK BIG! Does that sound like something we can all aspire to? Strive everyday to apply that same tenacity and unrestrained vision to your own lives and businesses.
This is where our Double Your Sales campaign comes in. If we all do a little bit more to reach, to grow, to dream and to work for our goals, there is no limit to what we can accomplish! Don't sell yourself short. Don't build yourself a "nice" business – don't settle for less than you deserve and can achieve. THINK BIG!
Keep Smiling,
Gregg Maughan
President, Forever Living Products


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Lately this has become a big question for a lot of people, especially when considering where to go and watch James Cameron's 3D blockbuster Avatar, and the questions has crossed my mind too, considering that there are cinemas with all of the three major 3D technologies where I live too. So here is a quick and short comparison between the three major solutions used in 3D movie theaters worldwide, along with information on which one I personally prefer, but you are also more than welcome to share your personal preferences along with the WHYs…
This one is the oldest of the three standards that is famous mostly because of the very big screens present in these cinemas, but they are still not very widely available around the world with most of the IMAX cinemas present in USA. Up until very recently IMAX 3D was only analogue with the movies being shot on large frame 70mm film in order to achieve good image quality on the larger screens these cinemas use, as compared to normal 35mm film. The digital version was introduced last year and still very few cinemas use that and the resolution and respectively the projection screen sizes for these implementations are not as big as on the analogue ones. IMAX uses big linear passive polarized plastic glasses for the viewers that do not provide the best possible experience. Anyway, getting back to the user experience, there is something very specific for IMAX 3D and that is the fact that the movies shown there are usually optimized for more pop-out screen effect than depth. This means that most of the time objects literally seem to pop out of the screen appearing as if you can touch them, kids do love this effect, but this is also more tiring for the brain. So usually longer movies are a bit of a problem to watch and Avatar is close to 3 hours, so you should be carefully consider this, especially if you feel a little "out of this world" when watching movies in an IMAX cinema. Some other drawbacks that are not always present and most of the people miss are the lower contrast in some dark scenes, a bit more ghosting of objects and problems refocusing your eyes quickly enough to follow the whole picture in fast action scenes and thus you might miss some important parts. Anyway IMAX 3D is certainly the most easy way to achieve the WOW effect with just about anyone that is watching his first stereoscopic 3D movie, but it this is not the first for you, then the other alternatives might be better…
This is a bit newer standard, but a digital one from its start… digital here meaning that the movies are recorded in a digital format and the projectors being used are also digital. RealD 3D cinemas uses circular polarized plastic glasses instead of linear polarized to provide better user experience when watching stereoscopic content. Circular polarization is considered to be better, because viewers are able to move their head as they like without the loss of the 3D depth effect. With the linear polarized glasses you have to be a bit steady, not moving around too much and sometimes you might have trouble finding the right position for your head in order to achieve the best effect when watching the movie to fully enjoy it. The circular polarized plastic glasses used here are also cheap to produce, but this technology requires the use of more expensive silver screen for projection which makes it a bit more expensive to implement. Still at the moment RealD is the most widely used standard for stereoscopic 3D movie projections all over the world, so you will most likely have one of these cinemas where you live. The immersion experience with RealD is a bit different compared to what you get at IMAX 3D projections as here the depth perception is of actual depth so the action is more going inside the screen, and not popping out of it. This does not make things less impressive, although some people might get a little disappointed at first if they were expecting to have the IMAX 3D pop-out effects, but after some time of watching they still get the feeling they are right in the middle of the action. This way of going more in the projection screen and not out of it is also easier on your brain as it is not that overloaded with information and is considered better for longer movies. Also it is easier to keep track of quick action scenes and the ghosting is usually less, so most of the people prefer this technology, although it is still not perfect.
Dolby 3D
Also known as Dolby 3D Digital Cinema is the newest of the three technologies for stereoscopic 3D movie projection and as you can guess not only by the name it is as well digital like RealD. A lot of people find that Dolby 3D is the best stereoscopic 3D technology for them to watch movies in the cinema. Here we also have the typical cinema style plastic 3D glasses that use a bit more specific passive filters related to the main colors we see which is by far considered to provide the best results. Of course this special type of polarization brings the cost of the glasses up compared to the normal linear or circular polarized glasses the other technologies use, but there the projection screen doesn't have to be specific (Dolby 3D at home, anyone?). Dolby 3D provides better color reproduction (colors look a bit brighter and more vivid) and a sharper image with more details visible (especially in darker areas), better contrast and almost no ghosting of the objects you see on the screen, which also are not that much popping out of the screen like in IMAX 3D, but rely more on inside depth, like with RealD. Still the stereoscopic 3D experience here is yet again not perfect as you might have trouble with the quick refocusing of your eyes on some objects moving fast from the back to front and some people might have weird troubles seeing the right colors some rare occasions.
And after all this you can say that it is still mostly a matter of personal preferences where you'll watch 3D movies, but sometimes you might not have IMAX 3D cinema around or any other technology. Have in mind that with the case of Avatar, it is also being shown in some 2D cinemas, but that will be too stupid to do when the movie has been made especially to be watched in 3D. The only thing I don't like about IMAX is that after about 40 minutes I'm a bit tired and I probably will have trouble watching a movies that is much longer than that. As for RealD and Dolby 3D for me there is hardly any significant difference between the quality and experience you get in cinemas equipped with one or the the other technology, although Dolby 3D seems to be slightly better. And don't forget that sometimes not well enough built or equipped 3D movie theater can also ruin everything with the one at fault not the technology being used… ;)


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DomainJedi needed a new logo design and created a contest on 99designs.
A winner was selected from 47 designs submitted by 24 freelance designers.
This is a new personal video player that allows people to organize, share, and download videos from YouTube.com and other websites.
This logo must be:
*Easy to read small, medium and large on screen.
*Creative and Cool.
Feel free to use any colors and come up with any idea you have.
Find out how a design contest works or learn more about our logo design services.


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–It feels like it's been an age since the election, and my last post. I'm still crying about it. I don't if I will ever stop. Thanks to everyone who sent me a little note (or even an email!) about my absence. I truly appreciate it. Many times I've pulled my chair up to the keyboard but I just couldn't get very far. In addition to the turmoil and stress in the country, my little world has been rocked further by health problems in myself and my immediate family. This year has been incredibly tough, and I know that many of you feel the same way. Sad stuff aside, let's talk about what I've been up to!
–Anthony has been on two week-long work trips across the country this month, further making any blog updating even more challenging. He's hadn't been in an airplane since a trip he took to Guatemala before he met me. It's been a learning experience for both of us, and I feel pretty battle-hardened in the single parenting-while-ill arena.
–Earlier this month I was unintentionally live for two and a half minutes on Facebook. Join me next week for my unintentional podcast! This isn't the sort of thing that typically happens to people, unless you are me. This is the sort of ridiculous thing that happens to me all the time. I apologize for anyone watching and wondering when something exciting is going to happen. Spoiler alert! It never does! Though I do sing an improvised rain song to Elias, as it was raining.
–We've hosted an annual Christmas party for friends for years now, and I thought that with Anthony's travelling schedule and my illness and the general terribleness of the year that we might have to skip it. At the eleventh hour, though, after talking to my friend Laurel, I decided that getting together was probably something we all really needed. I'm glad I did it, as this year we had the most epic Thrift Store Gore Gift Exchange ever, plus we somehow found a 7+ minute version of Last Christmas to sing via karaoke.
–I'm on a short run of steroids again to deal with a respiratory problem that turned chronic. Being on steroids is like riding on a jerky, out-of-control park swing. Swing goes up, and I love steroids! I have energy to keep up, even when plans change! Swing goes down, and I hate steroids! I'm moody and anxious and sad and sleepless! It's exhausting without the possibility of rest. Thankfully I'm just on it for the short term this time.
–Isobel told me she wants to give all the cats Christmas presents. Specifically, she wants to get our cats a kitten.
–I knew ordering an inexpensive Christmas tree from China was risky, but I needed a tree I could afford that could get here in time for the last-minute Christmas party. You guys, take a look at our "full size", "6 foot tall" Christmas tree. Even my cat is underwhelmed. It's all decorated now and I think it looks lovely, but I still giggle to myself every now and then when I walk past.
–I was playing Goat Simulator with Isobel when she suddenly says "WARNING: this game is extreme amounts of fun"
–Someone found a migrating tarantula at my MIL's school, if you want to have nightmares forever.
–One night Isobel rolled over and, in her sleep, clearly said, "Toys."
–Elias' two favorite phrases are, "No way, pants!" and, "I'm cray cray!" (I guess I may have said he was cray cray once or twice.)
–Isobel: "Kingston, you can call me any time! But not like literally any time."
–Isobel: I want a job at See's Candy! //Me: You can't just eat the candy, you know. //Isobel: *looks offended*.
Last night I spotted Dat Boi at a thrift store
San Bernardino police also said they generally recommend people don't confront armed robbers, "Unless you have a bunch of dildos," he added.
THRIFT STORE GORE: I found this in a charity shop. It used to sing a tune, now all it says is "Skin".
Look, it's Adam and Eve, not Florence and the machine.
"I do what I want, cat face" is my new burn.
This idiot was trying to make a racist announcement and this guy kept yelling NOOOOO in his face lmao. Plan: Deploy an army of Screaming Goats to every elected official in the land.
They're young… They're in love… They eat lard.
This should have been my patronus if we are being honest
[adam sandler voice] oh yesh das right
At my friend's church, the church cat has evicted the baby Jesus from the manger.
This is far and away the best Nemesis GIF I've made so far.
Fun and silly threads still exist on here, everyone. There's the twitter I know and love.
He's still learning about glass.
Just re-arranged my friend's DVD collection. How long before he notices?
When you're anxious but trying to act cool.
found this this garfield comic strip on my phone where jon has a vibrator in his ass.
the greatest parade footage ever, if we're being honest.
Many stores already carrying 2018 desk globes.
Hans Christian Andersen's The Snow Peen.
Atlas rolled around in some chalk and now he's a magical rainbow floofer.
What happens if we got to pick our name and occupation right after elementary school.
I would like to share a yak flip with you.
Just like Tony the Tiger & the Trix Rabbit, Honey Bunches of Oats unveils its new mascot, Your Mom's Boyfriend Jeff!
Col. John Glenn stained glass, Church of the Good Shepherd. Goodbye, Space Hero.
My new ringtone. Every time the darkness closes in today I'm going to think about that Pokémon kid playing sandstorm on a recorder till it passes
INDIVISIBLE: A Practical Guide for Resisting the Trump Agenda.
Support Aleppo's White Helmets.
"I don't take a good day for granted", and other powerful statements from people with Crohn's.
John Glenn's true hero: Annie Glenn. She worked against a huge disability and then used her platform to help others. What an amazing couple.
DIY Terrarium Christmas Ornament Tutorial
12 Creative, Thrifty Ways To Wrap Gifts


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The Czar Will Rule
President Obama's real czar, "pay czar" Ken Feinberg, who has real power, brushes aside such claims even as he prepares to issue his Gosplan-style edicts on future and even past pay agreements:
The Obama administration's pay czar says negotiations over executive compensation with the seven companies that received the biggest federal bailouts have been "a consensual process'' — not a matter of forcing decisions on them.
"I'm hoping I won't be required to simply make a determination over company objections,'' veteran Washington attorney Kenneth Feinberg told the Chicago Bar Association in a speech.
But note: he's "hoping" he won't have to impose his own view. He's hoping the companies will accede to his power without complaining. But the fact remains, he doesn't have to get their consent. He "has sole discretion to set compensation for the top 25 employees of each of those companies," and his decisions "won't be subject to appeal." Or, as Feinberg himself puts it,
The statute provides these guideposts, but the statute ultimately says I have discretion to decide what it is that these people should make and that my determination will be final. The officials can't run to the Secretary of Treasury. The officials can't run to the court house or a local court. My decision is final on those individuals.
That's power. So where is Doonesbury? We need him to update his classic 1970s "energy czar" strips.


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Photography Talk Chapter Two Video from John Keatley on Vimeo.
I hope you enjoyed the first video of my photography talk. As promised, here is the second video, and number three will be rolling out very soon also. The third one will be the Q&A session. I cover a lot of ground in this video including working with celebrities, but the main points are focusing on what you are trying to show in your work, and taking control to make it happen. Some of you have asked which camera these videos were shot on and although I have recently started to shoot video on the Canon 5D Mark II, I actually used this bad boy to film my talk.


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Health & Wellness
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Jan 23 – Jan 26 all-day Kauffman Center
*dates, times, and ticket prices vary Call this live production pure visual candy: enticing, bright and sweet. This adaptation of Charlie and the Chocolate Factory blends the best songs from the 1971 film with new music from Hairspray's composers.
Jan 23 – Jan 30 all-day Screenland Armour
One of the nation's premier genre movie festivals happens right here in Kansas City in January. Movie Maker recognized the event as one of the best horror fests in the country, and programming has grown to include live podcast recordings, a short film showcase and other fun oddities. Find the complete schedule here: https://panicfilmfest.com/schedule/
Jan 24 – Jan 25 all-day Kansas City Convention Center
Meet all your favorite Royals stars this offseason for autographs. It's the perfect holdover before opening day for the boys in blue on March 26. Schedule: Friday, January 24 12:00 p.m. – 2:00 p.m. | Exclusive access for Season Ticket Members 2:00 p.m. – 9:00 p.m. | Open to all fans Saturday, January 25 9:00 a.m. – 11:00 a.m. | ...
Jan 25 @ 7:30 pm – Jan 26 @ 10:30 pm Sprint Center
The Cowboy rides again when George Strait returns to Kansas City six years, nearly to the date, after what was supposed to be the country icon's final Kansas City performance.
Jan 26 @ 10:00 am – 4:00 pm The Nelson-Atkins Museum of Art
Ring in the Year of the Rat, seen in Chinese culture as a symbol of wealth, at the Nelson's annual celebration, taking in the museum's extensive Chinese art along with performances, calligraphy demonstrations and food.


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OnePlus 7T dskinz back skin
With this dskinz wrap / skin for your OnePlus 7T dskinz back skin you create a unique appearance and protect your backside from scratches and drops!
What is a skin?
A skin is a wrap made especially for your OnePlus 7T dskinz back skin. Think of it as a car wrap only with more protection. With a margin of not even a hair, a dskinz skin with precision is made in the Netherlands for your device. Our skins really feel like the material you have chosen, everyone will be surprised at the quality and looks of your OnePlus 7T dskinz back skin.
Superior quality, easy as 1,2,3.
A dskinz skin is easy to apply without air bubbles because we use a unique material of 3M. This contains air ducts and therefore you will always create a sleek and very cool look with your dskinz OnePlus 7T dskinz back skin. Watch our video on our page How-to how to apply a skin in a few simple steps
No messing around, only quality
You can always remove and no residue will remain on your OnePlus 7T dskinz back skin. The only thing left is a scratch-free back that you can wrap with a new unique different color!
Extra protection
A dskinz skin only works very well, but you can of course also use it with a transparent case for extra protection, so we have the option for many models to add an Anti-Shock case for your OnePlus. We have created dskinz to personalize, protect and preserve your original OnePlus 7T dskinz back skin.
Do you have any questions? Let us know, we are here to awnser your questions!


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Walt Stoll passed away on Thursday, August 11, 2011. Volunteers, including Jan DeCourtney, CMT (co-author of Recapture Your Health and Director of the Stoll Foundation for Holistic Health) are continuing to run the bulletin board and to answer questions based on Dr Stoll's teaching and their own experience.
Here is Walt's obituary.
Here is Walt's obituary.
Walt Stoll, MD has practiced medicine for more than 30 years, most of that time as a Board Certified Family Practitioner. The last 17+ years have been spent combining as many other healing philosophies with Conventional Medicine as he could learn enough about to evaluate. Now Dr. Stoll would like to share this information with you.
- New Visitor FAQ
- Visit the ASK DR STOLL Bulletin Board (includes Site Search)!
- Archives on popular topics
- Wonderful Symptoms and Diseases Quick Reference Guide and Glossary graciously provided by RocketHealer Jim++!
- Read about Dr Stoll's new book co-authored with Jan DeCourtney, CMT: Recapture Your Health.
- Read about Dr Stoll's book: Saving Yourself from the Disease Care Crisis.
- See our budding links page!
- Donate to the Stoll Foundation.
- Subscribe to our free e-newsletter to be notified of upcoming events, new releases, and health tips.


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Product features:
Managed 48-Port 10/100 Stackable Switch + 4 Gigabit Ports + 2 Combo SFP SlotsEOL
The DES-3028/3052 series switches are managed Layer 2 Ethernet switches designed as the premium devices in the entry-level network management category. These switches offer very rich functions to let SMB and even enterprises set up a secure and effective departmental network at affordable cost. Outstanding features include high port densities, 41Gigabit uplinks, Power over Ethernet support , comprehensive network security, granular bandwidth control and extensive network management. With these switches, businesses can now optimize their networks at both the function and cost levels for maximum results.
High Port Density & PoE Support. The DES-3028/3052 series provides choices of 24 and 48 Ethernet ports, with or without Power over Ethernet (PoE), in low profile rack-mount cases. Each switch is equipped with 2 Gigabit uplinks, with the SFP supporting both fiber Gigabit and 100BASE-FX fiber connection for specific applications.
Security & Availability. The DES-3028/3052 series supports many security features including Access Control List (ACL), 802.1X Port-Based/MAC-Based Access Control, 802.1X Guest VLAN, and RADIUS/TACACS+ authentication. T o prevent malicious attack and virus/worm affection from overwhelming the switch with unnecessary workload, the DES-3028/3052 series provides D-Link Safeguard Engine and CPU Interface Filtering functions to increase the switch's reliability and availability.
Resilience/Performance Enhancement. To enhance network resilience, the DES-3028/3052 series provides Spanning Tree protocols, including 802.1D, 802.1w and 802.1s for redundant bridge paths. 802.3ad Link Aggregation provides the aggregated bandwidth between switches or server, For Quality of Service (QoS), it supports 802.1p Priority Queues and packet classification based on TOS, DSCP, MAC, IPv4, VLAN ID, Protocol type, User Defined Packet Content, enabling Internet voice, video and streaming media applications to run smoothly.
Traffic Monitoring/Bandwidth Control. Network administrators can define throughput levels for each port to manage bandwidth. The bandwidth control feature provides fine granularity with the ability to define limits down to 64Kbps segments. Broadcast storm control can reduce the level of damage that a virus attack can do to the network. The switch provides IGMP snooping to control multicast transmission, and port mirroring to facilitate diagnostics.
Management. The DES-3028/3052 series supports standard-based management protocols such as SNMP, RMON, Telnet, web-based GUI, SSH/SSL security authentication and DHCP Relay Option 82. With DHCP auto-configuration, the administrator can pre-set configurations and save them in a TFTP server; individual switches can boot their IP from the server and load in the pre-set configurations. D-Link Single IP Management simplifies and speeds up management tasks, allowing multiple switches to be configured, monitored and maintained from any workstation running a web browser through one unique IP address. A virtual stack of the DES-3028/3052 switches can be managed as a single object, with all units identified by a single IP address.
Support Resources


text: Get support Find your nearest Support Group Sunderland Support Group Our Support Groups are free to attend and are open to anyone affected by bipolar, including family, friends and carers. Find out more about what happens at a Support Group. Meets: 2nd Monday of every month. Time: 7.00pm - 9.00pm Postcode: SR2 7AQ


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Fighting stereotypes
We all generally value and respect the older people we love or know well. But our attitudes to other older people within the broader community can be different.
In many traditional societies, older people are respected as "elders". However, in other societies, older women and men may be less respected. The marginalization can be structural, for example enforced retirement ages, or informal, such as older people being viewed as less energetic and less valuable to a potential employer.
These attitudes are examples of "ageism" - the stereotyping of, and discrimination against, individuals or groups because of their age. Ageist attitudes can portray older people as frail, "past their sell-by date", unable to work, physically weak, mentally slow, disabled or helpless. Ageism serves as a social divider between young and old.
These stereotypes can prevent older men and women from fully participating in social, political, economic, cultural, spiritual, civic and other activities. Younger people may also influence these decisions in the attitudes they convey to older people, or even by building barriers to their participation.
Ageist stereotypes can also prevent us meeting the challenges of population ageing since they can prevent us asking the right questions or finding innovative solutions.


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"National University's integrative medical clinic is something that isn't comparable to any other school that I looked at. You're working with other health care professionals in the field, side by side."
"I chose National because it has a great reputation. National's preparation for the board exams is excellent. With the smaller class sizes, there is a lot of one on one. The instructors are always willing to help. They make sure you have the best education you can possibly get."
"I was impressed with the Introduction to Massage Course. It's a four-night course you can take before deciding whether you want to sign up for the entire program. If people take that course and then shop around at other schools, they'll understand pretty quickly that it's hard to beat National!"
"National University has an on-site clinic that integrates chiropractic medicine, naturopathic medicine, oriental medicine, and acupuncture. It's very helpful to work together with the other fields. I also like the clinic because you're not just massaging your friends. You're out there in the real world with real clients.""
"I like the way the curriculum is designed. There is plenty of repetition and application as you go deeper, and it provides a safe place to learn and make mistakes. It really fits my learning style. The people who teach here also work in the field. They bring real stories of real people and real experiences to class."
Follow our blog for notes, thoughts, news, and information on the field of massage therapy.


text: George Woodman began his career as an abstract painter, exploring color and structure in his work, then moved to photography in the early 1980s, a medium with which he has been experimenting ever since. A central member of the art community in Colorado, Woodman was part of the Criss-Cross Art Communications group (formed in the early 1970s) and among the founding members of the SPARK Gallery (founded in 1978). Woodman's is a family of artists, whose most famous member is his daughter, the late photographer Francesca Woodman. His black-and-white photographs of nude young women, often embellished with paint, remind viewers of Francesca's work while reflecting his own vision. As he explains: "My familiarity with her work and its importance has made me want to produce something that can't be confused with hers. I try to have a space which is my own."