text:
Iontotherapeutic devices, reservoir electrode devices therefore, process and unit dose
Provided are reservoir electrodes for iontotherapeutic devices which have two chambers; the first chamber is electrically connected to the iontotherapeutic device and is designed to contain electrolytic solution and the second chamber has ionized pharmaceutical dissolved in electrolytic solution. The two chambers are separated by a permselective membrane. The first chamber has means to inhibit increase in ionic content caused by the operation of the iontotherapeutic device. Also provided are unit dose forms adapted for insertion into the reservoir electrodes. The dose unit forms are made of crosslinked polymer and contain ionizable pharmaceutical which is released for absorption during operation of the iontotherapeutic process. Also provided are novel iontotherapeutic devices and processes.
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This invention relates to an iontotherapeutic device and reservoir electrodes therefore, for regulated transdermal systemic administration of ionizable pharmaceuticals (including ionizable biopharmaceuticals).
It also provides an iontotherapeutic process for transdermal administration of ionizable pharmaceuticals, particularly those which are otherwise transdermally absorbed to a small degree or not at all. The invention also relates to a unit dose in which an ionized pharmaceutical is dispersed. The unit dose is adapted to be assembled as a part of either the anode or the cathode, depending upon whether the ionized pharmaceutical is cationic or anionic, so that the ionized pharmaceutical will be delivered transdermally and then be absorbed systemically when the iontotherapeutic device is in operation.BACKGROUND ART
Many pharmaceuticals are required to be administered by injection. Other pharmaceuticals may be administered orally, but in some cases, there is inefficient absorption into the bloodstream to permit the pharmaceuticals to achieve the intended therapy. Also, with regard to oral administration, many orally administered pharmaceuticals undergo a high degree of destruction by the hepato-gastrointestinal first-pass metabolism. Often the metabolites of the first-pass metabolism cause unwanted biological activity or toxicity. In oral administration, there are variables which cause undesirable variations in the extent of gastro-intestinal absorption from subject to subject, especially in the case of some pharmaceuticals; and there are also associated problems of uneven blood levels resulting from an initial large absorption with attendant undesirable side effects or toxicities, and subsequent blood levels which are less than therapeutically optimal.
There has been an increasing interest in transdermal delivery. However, transdermal absorption of a number of pharmaceuticals has not been satisfactorily developed for adequate therapy, since they have not been absorbed transdermally to any significant degree.
Investigations have been carried out to explore the delivery of certain therapeutic agents transdermally by use of iontotherapy. Development of previous reservoir electrode devices have been reported, for example, by Sanderson et al., U.S. Pat. No. 4,722,726 and references cited therein.
It is highly desired to provide new and improved iontotherapeutic devices, reservoir electrodes therefore, and devices, reservoir electrodes therefore, and iontotherapeutic processes and unit dose forms for use therein and to provide further thereby therapeutic levels of systemically-active pharmaceuticals efficiently with a physiologically-acceptable low electric current.SUMMARY OF THE INVENTION
Provided by this invention is a pharmaceutical reservoir electrode for use in iontotherapeutic delivery of a pharmaceutical which is ionized and is contained therein, comprising:
a) a housing for said electrode;
b) a first chamber which contains an electrolytic solution to permit said iontotherapeutic delivery to take place and having present therein ion exchange resin in suitable form, which is capable of removing ions generated in the reservoir electrode in said first chamber as the iontotherapeutic delivery takes place;
c) an electrical connector to contact electrically the electrolytic solution contained in said first chamber and adapted to connect electrically with an iontotherapeutic device used for iontotherapeutic administration;
d) a second chamber for receiving said ionized pharmaceutical; and
e) a permselective membrane separating said second chamber from said first chamber, said membrane characterized by having pores preferably with permeability sufficiently low to inhibit substantial passage of said ionized pharmaceutical present in said second chamber into said first chamber during said iontotherapeutic delivery of the ionized pharmaceutical.
The second chamber can preferably be open for receiving a unit dose adapted to be inserted into and to be secured in the open second chamber. Alternatively, the second chamber can be closed, i.e., having a wall or membrane covering the open mouth of the chamber to make it a closed chamber. In this event, the wall member or membrane member must be compatible with the ionized pharmaceutical to be administered iontotherapeutically and to be stable dimensionally. The outside wall member must also have the characteristic of permitting the pharmaceutical in ionized form to pass through in order to be administered during the iontotherapeutic process.
The closed second chamber in this alternative is provided with an opening into which the solution of the ionized pharmaceutical can be filled into the closed second chamber.
To be used in conjunction with the open second chamber, are provided herewith unit dose forms. These can be inserted into the open mouth of the second chamber. The inserted dosage unit rests in intimate contact with the permselective membrane, which separates the said second chamber from the said first chamber. The dosage unit can have an outside wall portion and a peelable membrane or wall portion covering the base surface of the dosage unit which will be removed before insertion of the dosage unit into the open mouth of the second chamber. Likewise, the outer surface of the dosage unit can be covered with a peelable wall portion or membrane. In this type of unit dose, the pharmaceutical is present in a hydrogel unit dose wherein the dissolved pharmaceutical in ionized form can be uniformly dispersed in a suitable and compatible hydrophilic polymer. The exterior surface of the unit dose can be any suitable material which permits an intimate contact with the skin of the subject being treated with the ionized pharmaceutical present in the unit dose. In making the unit dose wherein a suitable hydrophilic polymer is utilized, a selection is made of the hydrophilic polymer which is compatible with the ionized pharmaceutical present in the unit dose, as well as being sufficiently dimensionally stable to permit storage, transportation and utilization of the unit dose in the iontotherapeutic device employed in administering the ionized pharmaceutical. The solvent used to dissolve the pharmaceutical which has been dispersed in the dosage unit can be removed if desired by evaporation. In this embodiment, the unit dose can be wetted when preparing the unit dose for insertion into the second chamber with a suitable amount of sterile aqueous solution, such as an aqueous buffer having suitable ion content and pH.
The unit dose consists of a crosslinked polymeric material which is in hydrogel form. The unit dose is desirably formed by polymerizing a combination of a solution of the ionized pharmaceutical and the monomeric material used in forming the crosslinked polymeric hydrogeled unit dose. Polymeric material and the crosslinking agent, as well as any required catalyst composition, must be selected which is comatible with the pharmaceutical employed. The pharmaceutical must not react substantially with or be degraded by the components of the polymerization composition, and must be stable in the presence of the ingredients of the final crosslinked polymeric unit dose. The polymeric composition must provide a crosslinked polymer which is substantially free of components that are biologically unacceptable.
It has been found suitable to employ acrylamide along with a suitable crosslinking agent such as bis-acrylamide and catalyst composition, to provide a crosslinked polymeric hydrogeled dosage unit. It has been found acceptable to incorporate insulin as the ionized pharmaceutical to be incorporated into the crosslinked dosage unit adapted to be inserted in position within the open second chamber.
Also, it has been found desirable to incorporate along with insulin or other peptide pharmaceutical an agent which will inhibit or prevent proteolytic degradation after the ionized pharmaceutical has been transdermally absorbed in the iontotherapeutic process. One suitable agent to inhibit such proteolytic degradation has been found to be a protease degradation inhibitor, such as aprotinin. Other peptide pharmaceuticals which are ionizable can be also used in conjunction with a suitable proteolytic degradation inhibitor, either a protease inhibitor or another effective inhibitor of proteolytic degradation, which is compatible with the dosage unit and biologically compatible with the pharmaceutical component as well as the skin and body of the subject being treated.
The ionized pharmaceutical solution can be contained in a unit dose form such as a disposable polymeric unit dose form to which a dosage amount of an ionized pharmaceutical solution (pH desirably at least about 1.0, 1.5 or about 2 pH units above or below the pKa or isoelectric pH of the ionized pharmaceutical if the pharmaceutical is peptide in nature) is dispersed in a polymer which is characterized by being compatible with the pharmaceutical as well as the skin, hydrophilic, and capable of releasing the pharmaceutical for iontotherapeutic transdermal absorption.
The unit dose form used with the reservoir electrode of the invention can also comprise a sterile solution of the ionized pharmaceutical contained within a closed reservoir unit dose form having a drug-releasing microporous membrane surface. The unit dose forms are prepared to provide the ionized pharmaceutical to be delivered iontophoretically through the skin of the subject treated and to provide iontotherapeutic transdermal absorption of a systemically effective amount of the pharmaceutical.
The unit dose forms are maintained covered to retain sterility until the desired time of iontotherapeutic administration. Alternatively, the unit dose forms can be sealed under sterile conditions in individual pouches.
The pharmaceutical reservoir electrode which will receive such a unit dose form is used as a part of a suitable iontotherapeutic device, which can be used to carry out the iontotherapeutic delivery and transdermal absorption of the ionized pharmaceutical. The pharmaceutical reservoir electrode is either a cathode or an anode depending upon whether the pharmaceutical is in anionic or cationic form, respectively. The iontotherapeutic device desirably provides, in the process, an iontotherapeutically effective and physiologically acceptable periodic pulse current with a specific waveform having an amplitude up to about 10 mA based on a reservoir electrode skin-contacting area of about 5 cm.sup.2 and an effective frequency of at least about 10 Hz up to about 50 KHz until the subject treated has received a pharmacologically-effective systemic dosage of the ionized pharmaceutical.
The pharmaceutical in the dosage unit can be selected from pharmaceuticals which can be ionized, including those which ordinarily are not transdermally absorbed through intact skin in an effective dosage amount, such pharmaceuticals including but not limited to insulins, vasopressin, heparin, growth hormones, glucagon, oxytocin, calcitonin and other macromolecular drugs as well as a number of others which can be provided in ionized form. A number of compounds which are naturally-occurring in humans, and which often are peptide in nature, are also included within this pharmaceutical group, many of which can be produced identically or as a related compound using DNA recombinant or other biological techniques.BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a cross section of a reservoir electrode device of the invention having first and second chambers, the open mouthed second chamber shown receiving a hydrogel dose unit having a peptide drug dispersed therein.
FIG. 2A is a cross section of a portable iontotherapeutic device which can be attached to a subject being treated iontotherapeutically, said device having integrated therein a reservoir electrode device of the type shown in FIG. 1 and a dosage unit of the invention being in operating position in the second chamber of the reservoir electrode.
FIG. 2B is a top plan view of said device with the dosage unit in place showing the receptor electrode of said device circumferentially positioned with reference to the installed dosage unit and spaced from said dosage unit by a non-conductive ring.
FIG. 3 is a partial cross section of another embodiment of a portable iontotherapeutic device of the invention showing a battery power source, liquid crystal display, integrated circuitry, a reservoir electrode of the invention, an installed dosage unit of the invention, a wrist band for attachment of the iontotherapeutic device to the wrist of the subject treated, said wrist band having a receptor electrode in the wrist band opposite the installed unit dose.
FIG. 4A is a graph showing passive release of insulin from a polyacrylamide dose unit follows Q Vs. t.sup.1/2 relationship.
FIG. 4B is a graph showing that an iontotherapeutic release follows Q Vs. t relationship.
FIG. 5 shows four graphs in which current has been applied in iontotherapeutic administration of insulin for increasing time periods - 1, 2, 3 and 4 hours, respectively. The increasing release rate (dQ/dt) of insulin from a polyacrylamide hydrogel dosage unit is shown to prolong with the increase in the duration of current application.
FIG. 6 is a graph showing modulation of the release rate (dQ/dt) of insulin from polyacrylamide hydrogeled dosage unit by multiple applications of current.
FIG. 7A is a graph showing passive release of vasopressin from a polyacrylamide hydrogel dose unit to follow Q Vs. t.sup.1/2 relationship.
FIG. 7B is a graph showing corresponding iontotherapeutic release to follow Q Vs. t relationship.
FIG. 8 is a graph showing iontotherapeutic release profiles of vasopressin and insulin from polyacrylamide hydrogel dosage units for 3-hour current application periods.
FIG. 9 is a graph showing iontotherapeutic release profiles of vasopressin and insulin from p-HEMA hydrogel dose units for a 3 hour current application period.
FIG. 10 is a graph showing iontotherapeutic release rates (dQ/dt) of calcitonin from polyacrylamide hydrogel dose unit for a 3-hour current application period.
FIG. 11 is a graph showing iontotherapeutic release profile of calcitonin from p-HEMA hydrogel dose unit for a 3-hour current application.
FIG. 12A is a graph showing iontotherapeutic permeation profile of insulin from polyacrylamide hydrogel dose unit across hairless rat skin for a 3-hour current application.
FIG. 12B is a graph showing iontotherapeutic permeation profile of calcitonin from polyacrylamide hydrogel dose unit across hairless rat sin for a 3-hour current application.
FIG. 13 is a graph showing iontotherapeutic permeation rate (dQ/dt) of vasopressin from polyacrylamide hydrogel dose unit across hairless rat skin for a 3-hour current application.DETAILED DESCRIPTION OF THE INVENTION AND THE PREFERRED EMBODIMENTS
FIG. 1 is a cross section of reservoir electrode 10 of the invention. The electrode has a housing 12, which can be made of a polymeric material or other suitable material which is non-conductive and dimensionally stable. Suitable polymeric material can be selected from high density polyethylene, polypropylene, polyoxymethylene, polycarbonate or the like. The housing 12 can be molded following conventional molding procedures. The housing is shaped so to form a cavity comprising the first chamber 14 and second chamber 16. The first chamber 14 and the second chamber 16 are separated by membrane 18. Membrane 18 is a permselective membrane which has pores which are preferably sufficiently small to inhibit the pharmaceutical molecules present in the second chamber 16 from substantial migration into first chamber 14 but are sufficiently large to permit full aqueous contact of the electrolytic solutions contained in the first and second chambers. A suitable permselective membrane is selected depending upon the pharmaceutical being iontotherapeutically administered, and the pH selected for the electrolytic solutions contained in the first and second chambers. Illustrative permselective membranes are commercially available as Nucleopore membranes, Millipore membranes, Spectra/por membranes and others. The permselective membrane is placed into housing 12 in intimate contact with the gel polymeric unit 20 contained in the first chamber 14. The permselective membrane is maintained in place by friction fit against the inside wall of housing 12, by adhesive to the housing 12, or by snap fit into a receptive groove which can be formed nto the inner wall of housing 12, or the like means to maintain the permselective membrane in place.
A hole is centrally disposed in the base of housing 12 to permit passage of electrical conduit 24, which is attached electrically to electrical contact 22. Electrical contact 22 can be formed of any suitable electrically conductive material to make intimate electrical contact with the gel unit 20. Electrical contact 22 can be suitably shaped from a metallic foil, e.g., from platinum foil. Gel unit 20 has dispersed therein suitable anionic or cationic resin particles 26. The resin particles are dispersed in the polymeric hydrogel unit dose 20 in a manner to inhibit an increase in the ionic content of the electrolytic solution of first chamber 20 during operation of the iontotherapeutic process wherein electrode 10 is an assembled element of the iontotherapeutic device used in carrying out the process. more full description of the preparation of gel unit 20 follows herein. The housing terminates with a flange 28, which extends outwardly in a direction perpendicular to the vertical wall of the housing. On the outer surface of flange 28, is present an adhesive layer 30, which adheres to the skin of the subject during iontotherapeutic treatment. Suitably, the adhesive layer 30 is protected during storage and shipment until the electrode is being readied for iontotherapeutic use by application thereto of a peelable film which is biologically acceptable and adheres until it is desired to remove by peeling. Shown also is unit dose 34, which is formed of a polymeric hydrogel. It is shaped into such dimension that it can be pressed into second chamber 16 to fill it and remain secured in place. The upper surface of dose unit 34 will be brought into intimate electrical contact with permselective membrane 18. The preparation of dose unit 34 will be described in greater detail hereinafter.
In illustration, a unit dose can be made using polyacrylamide as a hydrophilic polymer and insulin as the pharmaceutical. The pharmaceutical insulin is dissolved in an acrylamide buffer solution. A suitable aqueous buffer for use is a citrate buffer having a pH at least 1 and preferably at least 2 pH units below the isoelectric pH of insulin (pH 5.3--isoelectric point of natural commercial insulin). A suitable ionic strength is also used. A suitable buffer has been found to be a pH 3.6 citrate buffer, ionic strength 0.1M. It is convenient to use a buffer of higher ionic strength to permit dilution through addition of the pharmaceutical solution and other additions to enable a final desired ionic strength. Using a buffer of double the final desired strength has been found suitable.
To 100 parts by weight of the double strength buffer, 15 parts by weight of acrylamide can be added and stirred to dissolve the acrylamide, which provides a 7 percent by weight of acrylamide. To this is added a suitable crosslinking agent. For this purpose, bis-acrylamide has been used. An amount of 1.05 parts of the total volume of acrylamide buffer solution is added. To this solution, it has been found suitable to add a preservative agent. It has been found suitable to add gentamycin sulfate at about 50 micrograms/ml of the solution and 50 micrograms of bacitracin per ml of the solution. Also, it has been found desirable to add urea to the solution in a suitable amount, for example at a concentration of about 2 mg/ml solution (or other suitable agent) to minimize adsorption of the pharmaceutical to the polymer used to make the unit dose and further to inhibit the aggregation of the insulin molecules to form fibrils. The solution is stirred to form a uniform solution.
A catalyst system of ascorbic acid (0.1 percent, w/v), ferrous sulfate (0:0025 percent, w/v) and hydrogen peroxide (0.03 percent of 30 percent stock, w/v) has been found suitable to polymerize acrylamide in forming the unit dose.
The ascorbic acid and ferrous sulfate catalyst components are added to the acrylamide solution with stirring. Then, the insulin solution component is added to the acrylamide solution in a suitable concentration, a 100 IU/ml (3.8 mg/ml) concentration has been found suitable.
Amounts of the insulin-acrylamide solution are added to suitable molds of the shape of the second chamber of the reservoir electrode. Molds made of polyethylene tetrafluoride, sold under the designation Teflon, have been found suitable for use in making unit doses and a suitable amount of the solution to form an individual unit dose has been found to be 150 microliters. A greater or lesser amount can be used depending upon the volume of the second chamber of the electrode and other factors. Then, a suitable polymerizing amount of hydrogen peroxide (or other suitable initiator), is added to initiate polymerization. A 10-15 microliter dilution has been found suitable. The acrylamide-insulin solution is stirred gently for a brief period. In a short time, such as about one-half minute, polymerization occurs to provide a dose unit consisting of a transparent hydrogel unit dose containing insulin uniformly distributed. Sodium bisulfite can be used to remove, if desired, any remaining traces of acrylamide, as is known.
The insulin-containing unit dose can be evaluated for transdermal absorption property for iontotherapeutic administration using the Valia-Chien cell and procedure.
The above procedure in the alternative can be repeated using another polymer as the hydrogeled material. Again, monomeric material is employed and is polymerized in the presence of the ionized pharmaceutical, such as insulin, in illustration. The final polymeric hydrogel material is poly-2-hydroxyethylmethacrylate (referred to as p-HEMA). The p-HEMA polymer hydrogel can be prepared in crosslinked form by utilizing the following illustrative composition: HEMA, 40%; ethylene glycol dimethacrylate (referred to as EGDMA), 0.8%; suitable catalyst, such as the azonitrile catalyst, 2,2'-azo-bis-isobutyl nitrile (referred to as AIBN), 0.02%; water, 35%; glycerin, 25%. All the ingredients of this composition are mixed together. AIBN and EGDMA can be added in appropriate small quantities from concentrated stock solutions dissolved in ethanol. A mixture of HEMA, a crosslinker, initiator, water and a plasticizer (glycerin) can then be purged with nitrogen for a period of time to remove oxygen, for example, 5-30 minutes.
The polymerization mixture can then be added to a suitable molds, such as polytetrafluoroethylene molds. The molds are covered suitably by use of polytetrafluoride films. Polymerization is then carried out at an elevated temperature suitable for the polymerization, such as 90.degree. C. for an appropriate time. It has been found suitable to employ about one hour.
Upon polymerization, the final transparent hydrogel discs are removed from the molds and are extracted thoroughly with distilled water to remove residual polymerization mixture or components such as the HEMA monomer. It has been found that continuous extraction with distilled water for a 48-hour period is ordinarily sufficient. The dose forms provided are dried.
Upon completion of the extraction, insulin solution using pH 3.6 citric buffer can be used to saturate the dried hydrogel unit forms. The insulin solution used can suitably be 0.65 mM. The concentrated citric buffer is added as referred to above, i.e., 0.1 mM. Therefore, after a period of saturating the hydrogel disc, the insulin discs are removed from the insulin solution and are wiped to remove residual solution remaining on the surface of the unit doses. They are then placed back into the molds.
In summary, suitable momomeric materials can be employed along with suitable crosslinking agents to provide the crosslinked dosage unit containing in the final unit dose form a unit dose amount of a selected ionized pharmaceutical wherein the crosslinked polymer hydrogel is biocompatible, compatible with the ionized pharmaceutical and capable of releasing the ionized pharmaceutical to be administered in the iontotherapeutic process. Sufficient crosslinking of the hydrogel polymer should be provided to result in dimensionally stable dosage units. The final dosage unit should be free of unwanted polymerization composition residues such as residual monomer and catalytic components.
Also, if desired, certain pre-polymerized non-crosslinked polymers can be employed to intermix with an aqueous solution of a selected ionized pharmaceutical, which is appropriately buffered or adjusted in pH, for example, at least one or two pH units below the pka or the isoelectric point of the pharmaceutical if the pharmaceutical is peptide in nature. The polymer and aqueous buffer solution of the ionized pharmaceutical can then be crosslinked using a suit able crosslinking agent for the polymer which has appropriate crosslinking sites such as points of unsaturation. In making the selection of such polymers and such crosslinking agents, it must be born in mind the stability of the pharmaceutical in such final unit doses after the crosslinking and the adequacy of the release factor of the pharmaceutical to assure desired iontotherapeutic absorption is achieved.
As expressed above, suitable proteolytic degradation inhibitors or combinations thereof can be added to the insulin solution or other peptide solutions used in the dose unit preparation to inhibit proteolytic degradation upon the absorption of the pharmaceutical into the skin. For example, aprotinin, a proteolytic degradation inhibitor, can be added to the insulin solution (or peptide pharmaceutical solution) used in the unit dose preparation. It has been found that about 0.1 to about 0.2 mM concentration of the proteolytic degradation inhibitor is suitable, desirably a 0.15 mM concentration is used. It is desirable to employ a pH in the dose unit substantially below or above the isoelectric pH of the proteolytic degradation inhibitor employed.
Preparation of other unit doses can be carried out by selecting other ionizable pharmaceuticals including other peptide pharmaceuticals such as vasopressin, growth hormone, calcitonin and the like.
In carrying out the iontotherapeutic process using the unit doses and the reservoir electrode devices provided herein, an iontotherapeutic device for the administration is employed. An iontotherapeutic device as illustrated in FIG. 3 can be employed in this administration.
In carrying out the iontotherapeutic process of this invention, a dosage unit as provided herein is utilized with a reservoir electrode as provided herein. The electrode therapeutic device utilized is shown in illustration by FIG. 3. In FIG. 3, the power source 96 can be a suitable button type battery, such as a 6-volt battery. The integrated circuitry 100 utilized can be selected from known circuits for iontotherapeutic devices. It is desirable to utilize circuits as shown in International Patent Publication WO-88/00846, published Feb. 11, 1988, which is incorporated herein by reference. It is preferred to utilize integrated circuitry which provides periodic DC current in the iontotherapeutic administration. It is preferred to utilize pulse current in the administration of up to about 10 mA based on a reservoir electrode/skin-contacting area of about 5 cm.sup.2. Current density is suitably in the range of about 0.1 to about 1 mA/cm.sup.2, desirably about 0.5 to about 0.8 mA/cm.sup.2, with about 0.6 mA/cm.sup.2 having been found satisfactory. In the administration, it is preferred to use a periodic waveform in the square, triangular, sinusoidal, trapezoidal, or other acceptable geometric forms, or combinations thereof.
Further, the circuitry desirably provides an on/off ratio of from 1/50 to 10/1. Additionally, it is desired to utilize a physiologically acceptable repetition frequency of at least about 10 Hz up to about 50 KHz, or more if physiologically acceptable.
Some pharmaceuticals, especially certain relatively low molecular weight pharmaceuticals, can be iontotherapeutically administered using periodic DC mode or periodic wave mode. For example, the periodic DC mode can be "on" for about 0.5 to about 60 minutes, preferably about 1 to about 30 minutes per hour. During the intervening period during the hour, the device is in "off" position. The "on" can be more frequent or less frequent as desired to provide effective treatment. In the dosage currents, the on/off ratios in the dosage units and the devices described herein can be used or adapted to be used in the practice of the iontotherapeutic process of this invention.
A few hours duration of treatment each day following either procedure is ordinarily adequate, for example, two to ten hours, depending upon factors such as the pharmaceutical, the subject being treated, the iontotherapeutic factors selected and the like.
With regard to the making of the unit dose, there are a number of polymers which can be used to make the polymeric unit dose. In general, the polymer must be essentially nonionic, hydrophilic and compatible with the ionized pharmaceutical and the skin. The polymer used in making the dosage unit must permit the ionized pharmaceutical to be released during the operation of the iontotherapeutic device. The final polymers which are suitable in making the dosage unit are usually referred to as being in the category of hydrophilic polymers or hydrogels. These are preferably as pointed out above, selected from those that can be polymerized in situ. Also polymers which can be utilized can be selected from those which are pre-polymerized and have certain cross-linkable sites such as vinyl groups, hydroxy groups, carboxyl groups, amine groups, or other suitable groups which are suitable for crosslinking in making the unit doses of the invention. The particular polymer utilized is mixed with an aqueous solution of a pharmaceutical in which the pH of the solution is suitably adjusted to be substantially above or below the pKa or the isoelectric point if the pharmaceutical is peptide in nature.
With respect to the electrolytic solution present in the first chamber, it can suitably be in the form of a preformed electrolytic solution disc wherein suitable ionic exchange resin granules are suspended in the electrolytic solution having a suitable pH. The electrolytic solution discs can be formed, generally speaking, following the procedure described above for making unit dose forms. A monomeric material, crosslinking agent, aqueous buffer, catalyst composition, stabilizers, preservatives and other desired ingredients are added together with stirring. A desired amount of suitable resin granules are added and stirring or agitation is carried out adequately to get a thorough distribution of the selected ion exchange resin granules. Polymerization can be done as illustrated above with respect to the dose unit. The exact polymerization procedure and other procedures utilized in making this electrolytic disc unit for utilizing in the first chamber can be selected in accordance with the configuration of the cavity of the first chamber. As in the case of the dosage unit, the electrolytic disc is sufficiently polymerized and crosslinked to be dimensionally stable to hold the ion exchange resin granules utilized in uniform distribution.
The ion exchange resin granules are selected from cationic or anionic exchange resins. Cationic exchange resins have ion active groups with which cations react or are bound. The functional groups are normally acidic, for example are sulfonic, carboxylic or phenolic groups. Alternatively, the ion exchange resin can be anionic exchange resins which have ion active groups with which anions react or are bound. The anionic exchange can have in illustration a polyamine structure. Ion exchange resin used are water insoluble.
The particle size of the ion exchange resin can vary depending upon the ion exchange selected, the amount used, and other factors. It has been found that generally a particle size in the range of from 100 to about 200 micrometers, suitably about 150 micrometers. Suitable ion exchange resins of both anionic and cationic exchange types are available commercially for use in carrying out the invention.
Permselective membranes suitable for use in carrying out the invention are available commercially, as noted above. A permselective membrane will ordinarily be selected having pores with sufficiently low permeability with regard to the ionized pharmaceutical used to prevent substantial passage of the ionized pharmaceutical molecules into the first chamber. The permselective membranes are usually made of selected polymeric materials. The membranes will be selected which are compatible with the ionized pharmaceutical used in the iontotherapeutic administration, are stable structurally in its use in separating the first and second chambers and do not substantially interfere with the functioning of the desired iontotherapeutic process using the reservoir electrode having such permselective membrane.
Alternatively, the ion exchange resin granules present in the first chamber can be present in the form of a coating to a pre-formed polymeric lattice which has a shape to fit into the configuration of the first chamber. The lattice can be a series of concentric circles held in spaced relationship by cross members, can be in a form of an open celled matrix such as a honeycomb shape, or a type of ladder lattice form. Alternatively, the resin granules can be affixed to the bottom wall of the first chamber and/or to the sidewall portion of the first chamber. This can be accomplished by affixing to the bottom wall or the side wall or both a suitable resin film having suitable anionic or cationic resin as the need requires. Such resin films can be affixed as by following conventional procedures, for example, as by using heat sealing, a suitable adhesive or like procedures. In the event that resin film is applied to the side wall or the bottom wall or a lattice is used as described above or combinations thereof, the electrolytic solution can be present in the first chamber as a flowable solution, rather than being held in the crosslinked electrolytic polymeric disc. Also there can be utilized in making the first chamber to provide its capability of withdrawing ions generated during the iontotherapeutic process, a second membrane which can be placed contiguously to the permselective membrane 18 as shown in FIG. 1. Such resin film layer can be held in place by usual or customary means such as by clamping or adhesion on the periphery of the permselective membrane and the resin film layer. Again, combinations of such resin film layer and coatings on the bottom wall or side wall or the resin coated lattice or with the electrolytic unit disc having uniformly suspended therein resin granules.
When granules are utilized, they will be selected depending upon the amount of resin that is used, the amount of ions generated during the iontotherapeutic process utilized, the pharmaceutical utilized and the length of iontotherapeutic administration and other factors. It will be apparent to those skilled in the art by the description herein what the operative amount will be in a specific iontotherapeutic process carried out according to this invention.
With respect to the receptor electrode, there will be provided polymer hydrogel discs or other suitable element so as to adapt to the particular iontotherapeutic device utilized. Likewise, the shape will be such that it is adapted for use with the particular receptor electrode utilized by the iontotherapeutic device used. In illustration, FIG. 2B shows the receptor electrode to be in the form of a cylinder that fits within the housing of the iontotherapeutic device in the provided slot and as shown is concentric with the reservoir electrode and spaced therefrom by a non-conductive insulating cylinder, which cylinder is in intimate contact with both the reservoir dosage unit as well as the receptor electrode. Additionally, as shown in embodiment FIG. 3A, it is shown in this wrist-type iontotherapeutic device that the receptor electrode is present in the band surrounding the wrist in a cavity which is on the opposite side of the wrist from the reservoir electrode. Such hydrogeled disc is made in a shape to be secured in the cavity provided in the wrist band.
The following examples are illustrative of the invention but are not intended to be limiting.EXAMPLE 1
Insulin at a concentration of 100 IU/ml (3.8 mg/ml) is dissolved in an acrylamide buffer solution before the solution is gelled with the addition of an initiator.
The buffer solution used is a pH 3.6 citrate buffer having an ionic strength of 0.1M and is prepared using the following formula:
______________________________________ Anhydrous citric acid 26.2 g Disodium hydrogen phosphate 9.0 g Water, qs to make 1000 ml ______________________________________
The buffer is prepared as a stock in double strength, so that allowance remains for the addition of monomers, peptides, and other additives before the volume is made up to the final desired concentration. To this buffer solution, 15% acrylamide (by weight) is added and dissolved. This is followed by the addition of bis-acrylamide (crosslinker) to the acrylamide solution in a concentration of 7% based on monomer weight (1.05% by weight of the total volume of the final solution). Before the addition of insulin, this solution is preserved by the addition of gentamycin sulfate (50 ug/ml) and bacitracin (50 ug/ml). Also, urea is added thereto in a concentration of 2 mg/ml, to minimize adsorption and self-aggregation of the insulin molecule. The catalyst system for polymerizing the monomer (acrylamide) is also added to this solution, delaying the initiator for the final step. The composition of the catalyst system is as follows:
______________________________________ Ascorbic acid 0.1% (w/v) Ferrous sulfate 0.0025% (w/v) Hydrogen peroxide 0.03% of 30% stock (w/v) ______________________________________
Insulin is then added to this solution in a concentration of 100 IU/ml (3.8 mg/ml). This solution is then pipetted (150 microliters) into polyethylene tetrafluoride cylindrical molds (having a circular cross section of 10 mm and then it is polymerized in situ by the addition of hydrogen peroxide at a suitable dilution such as to have the requisite concen-tration in 10-15 microliters of dilution. The initiator is added with gentle and brief stirring. Polymerization occurs within about half a minute and very uniform, transparent hydrogel unit dose discs containing the insulin are obtained in the mold. This unit dose is then mounted on the skin in the Valia-Chien cells for in-vitro permeation studies by following the standard procedure as previously referred to.
For permeation study, freshly-excised skin from hairless rats is mounted on the Valia-Chien cells. The device with the exposed side of the hydrogel is placed on the stratum corneum surface of the skin and the donor half-cell remains empty. Current is applied to the other side of the hydrogel using a platinum foil electrode placed on the surface of the hydrogel and iontophoretic delivery is thus accomplished. Samples are taken from the receptor half-cell and are analyzed by radiotracer or radioimmunoassay for extended periods of time.
If desired, aprotinin, a protease inhibitor, can be added to the solution before gelling, in a concentration of about 0.15 mM. This will result in iontophoretic delivery of aprotinin along with insulin and thus will provide protection against proteolytic degradation of insulin in the skin. For the use of the permselective membranes, a Spectra/Por membrane, with a molecular weight cut-off of less than 3,500 can be used to prevent the diffusion of insulin into the first chamber. For the use of ion exchange resins, an appropriate resin in suitable form can be dispersed into the hydrogel matrix in suspension before gelling is carried out.
This procedure can be easily extended to other peptides such as vasopressin or calcitonin or to non-peptide drugs as well.EXAMPLE 2
The p-HEMA hydrogel is prepared using the following composition:
______________________________________ 2-hydroxyethylmethacrylate (HEMA) 40% Ethylene glycol dimethacrylate (EGDMA) 0.8% 2,2'-Azo-bix-isobutyronitrile (AIBN) 0.02% Water 35% Glycerin 25% ______________________________________
The above ingredients are all thoroughly mixed together. AIBN and EGDMA are added in microliter quantities from concentrated stock solutions in ethanol. This mixture of monomer (HEMA), crosslinker (EGDMA), initiator (AIBN), water and plasticizer (glycerin) is then bubbled with nitrogen gas for 20 minutes to remove dissolved oxygen. The solution is then added to polytetrafluoroethylene molds and the filled molds are covered with films. Polymerization is then carried out at 90.degree. C. for 1 hour. Following this, the transparent hydrogel discs are removed from the teflon molds and are extracted with distilled water for 48 hours to remove any residual monomer. Following the extraction pro-cedure, insulin is incorporated into the hydrogel discs by soaking the hydrogel discs in a 0.65 mM solution of insulin in pH 3.6 citrate buffer. The composition of the citrate buffer is the same as given in Example 1. After 24 hours, the hydrogel discs are removed from the insulin solution, wiped free of adhering solution and then placed back into the mold device. Skin permeation studies are then carried out in the same manner as described under Example 1.EXAMPLE 3
Dose units made following generally the procedures of Examples 1 and 2 are evaluated for their diffusion and permeability using iontophoresis. The following conditions of iontophoresis are used: periodic DC current density of 0.62 mA cm.sup.2 ; square periodic waveform; on/off ratio of 1:1; repetition frequency of 2KHz.
Results of the evaluation are shown in the following Tables:
TABLE 1 ______________________________________ A comparison of diffusion coefficients for the release of peptide pharmaceutical from unit doese under iontophoresis. Diffusion Coefficient (cm/s) Pharmaceutical Mol. Wt. Polyacrylamide p-HEMA ______________________________________ Insulin 5808 1.32 .times. 10.sup.-6 5.08 .times. 10.sup.-17 Calcitonin 3418 3.80 .times. 10.sup.-6 8.01 .times. 10.sup.-6 Vasopressin 1084 5.42 .times. 10.sup.-6 1.48 .times. 10.sup.-6 ______________________________________
TABLE 2 ______________________________________ A comparison of permeability coefficients for the permeation of peptide pharmaceuticals from unit doses under iontophoresis. Pharma- Mol. Permeability Coefficient (cm/s) ceutical Wt. Polyacrylamide p-HEMA Carbopol ______________________________________ Insulin 5808 3.12 .times. 10.sup.-9 6.54 .times. 10.sup.-9 Calcitonin 3418 6.20 .times. 10.sup.-8 1.95 .times. 10.sup.-8 0.69 .times. 10.sup.-8 Vasopressin 1084 6.16 .times. 10.sup.-7 1.06 .times. 10.sup.-7 2.74 .times. 10.sup.-7 ______________________________________EXAMPLE 4
Evaluation of dose units made generally following the procedures of Examples 1 and 2 have been made following the iontophoretic procedure and conditions of Example 3. Results of the evaluations are shown in FIGS. 4-13.
1. A pharmaceutical reservoir electrode for use in iontotherapeutic delivery of a pharmaceutical which is ionized and is contained therein, comprising:
- a) a housing for said electrode;
- b) a first chamber which contains an electrolytic solution to permit said iontotherapeutic delivery to take place and having present therein ion exchange granules which inhibit increased ionic content through ion generation in the electrode in the first chamber as the iontotherapeutic process takes place;
- c) an electrical terminus to contact electrically the electrolytic solution contained in said first chamber;
- d) a second chamber for receiving a unit dose of said ionized pharmaceutical, and
- e) a permselective membrane separating said first and second chambers, said membrane characterized by having pores with sufficiently low permeability to inhibit substantial passage of said ionized pharmaceutical present in said second chamber into said first chamber, said permselective membrane being substantially free of ion exchange sites.
2. An electrode of claim 1 wherein the unit dose is a crosslinked hydrophilic polymer unit dose adapted to fit into and be securely held in the second chamber, which chamber has an open mouth, said unit dose capable of retaining an aqueous solution of an ionized pharmaceutical and releasing said pharmaceutical by iontotherapeutic process.
3. An electrode of claim 2 wherein said unit dose is a crosslinked acrylamide polymer.
4. An electrode of claim 2 wherein said unit dose is a crosslinked p-HEMA polymer.
5. An electrode of claim 2 wherein said unit dose contains an ionized peptide pharmaceutical.
6. An electrode of claim 5 wherein the polymer of the unit dose is selected from the group consisting of acrylamide polymers and p-HEMA polymers.
7. An electrode of claim 1 wherein the pH of the aqueous solution of said ionized pharmaceutical is at least 1.5 pH units below or above the pKa or isoelectric point, if said ionized pharmaceutical is a peptide.
8. An electrode of claim 7 wherein said pharmaceutical is insulin.
9. An electrode of claim 1 wherein said first chamber is filled with a crosslinked hydrophilic polymer disc which is conductive, filled with an electrolytic buffer and has dispersed therein ion exchange resin granules capable of inhibiting increase of ionic content during iontotherapy.
10. An electrode of claim 9 wherein the unit dose is a crosslinked hydrophilic polymer unit dose capable of retaining an aqueous solution of an ionized pharmaceutical and releasing said pharmaceutical by iontotherapeutic process.
11. An iontotherapeutic device comprising a pharmaceutical reservoir electrode as defined in claim 1.
12. A device of claim 11 wherein said device is capable of providing a periodic DC current having a current density of about 0.1 to about 1 mA/cm.sup.2 of area of contact of the electrode with the skin of the subject being treated.
13. A process for iontotherapeutic administration of an ionized pharmaceutical to a subject desiring such therapy, comprising the steps of:
- a) applying to the skin surface of the subject a reservoir electrode as described in claim 1, said reservoir electrode containing an electrolytic solution in the first chamber and containing an ionized pharmaceutical solution in the second chamber;
- b) applying to the skin of the subject a second electrode spaced from said first reservoir electrode; and
- c) supplying current to the electrode which are electrically connected to cause iontotherapeutic administration of an effective amount of the ionized pharmaceutical to the subject from said first reservoir electrode.
14. A sterile unit dose adapted to be removably inserted into the receiving chamber of a reservoir electrode of a transdermal periodic iontotherapeutic system, said unit dose to be used in electrical contact with intact skin to be iontotherapeutically treated to administer transdermally a systemically effective dose amount of an effective and transdermally absorbable amount of an ionized pharmaceutical; said unit dose containing a sterile solution of said ionized pharmaceutical dispersed therein having an iontotherapeutically effective and physiologically acceptable pH at least about one pH unit lower or higher than the pKa or isoelectric point of said pharmaceutical; said unit dose adapted to permit said pharmaceutical to be released upon application to the reservoir electrode of an effective DC current; said unit dose made of a crosslinked, hydrophilic polymer and being dimensionally stable.
15. A unit dose of claim 14 in which the ionized pharmaceutical is contained and uniformly dispersed in the crosslinked polymer unit dose in which the polymer used in making the unit dose is essentially non-ionic, hydrophilic and essentially compatible with said pharmaceutical and the intact skin to be treated.
16. A unit dose of claim 14 in which the polymer is an acrylamide polymer.
17. A unit dose of claim 14 in which the polymer is a methacrylate type.
18. A unit dose of claim 14 wherein the ionized pharmaceutical is a peptide.
19. A unit dose of claim 18 wherein the pharmaceutical is selected from insulin, vasopressin and calcitonin.
20. A unit dose of claim 18 wherein there is present in said unit dose an effective amount of a proteolytic degradation inhibitor.
21. A unit dose of claim 14 characterized by the water of said aqueous solution of said pharmaceutical has been removed.
Type: Grant
Filed: Sep 25, 1990
Date of Patent: Oct 5, 1993
Assignee: Rutgers, The State University of New Jersey (New Brunswick, NJ)
Inventors: Yie W. Chien (North Brunswick, NJ), Ajay K. Banga (Rochester, NY)
Primary Examiner: Stephen C. Pellegrino
Assistant Examiner: Michael Rafa
Attorney: Leroy G. Sinn
Application Number: 7/587,406
International Classification: A61N 130;


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Rationality is an essential instrument in humanity's quest for knowledge, yet the practical pursuit of knowledge often ignores or violates fundamental principles of rational inquiry or overlooks the inherent limitations in the use of rationality as an instrument of knowledge. This project will explore the philosophy and practice of rationality as it is applied in various fields of knowledge to identify common deviations and limitations and propose ways to compensate for the limits to rationality.
Paper & Presentation by Simeon Anguelov at "Humanities in the Contemporary World"in Montenegro on June 7-9, 2012
Project Scope
For more information, contact Project Leader.

subset: commoncrawl


text:
Select Employer Groups: Mutually Beneficial Banking
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text:
NEW YORK (AP) The New York Mets have signed right-hander LaTroy Hawkins to a minor league contract with an invitation to spring training.
The Mets announced the deal Thursday.
The 40-year-old Hawkins went 2-3 with one save and a 3.64 ERA last season in 48 games for the Los Angeles Angels.
In an 18-year career, Hawkins has appeared in 871 games - 98 starts - for the Twins, Cubs, Astros, Brewers, Rockies, Giants, Angels, Yankees and Orioles. He is 65-88 with 88 saves and a 4.45 ERA.


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You'll feel totally relaxed with help from the pure gel seat cushion on this reclining chair. Plenty of support comes from the attached back pillows and arm cushions, while the power recline makes sitting back easy. This recliner gives you a cozy seating solution without sacrificing contemporary style.
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text:
I can't seem to access anything having to do with personal messaging or member profiles.
Below is a partial list of of Error URLs, if that helps:
Needing a hand.
Started by LoreKeeper , Jul 24 2012 03:08 AM
1 reply to this topic
Posted 24 July 2012 - 03:08 AM
"Questio Pro Verum"
Posted 24 July 2012 - 07:54 AM
Unfortunately, due to spammers and other pests Ghost Village has had to take action. What was done is to restrict all new members from access to member profiles and the PM system until they reach 30 posts. I see you are a new member and this is the reason for your difficulty. However once you have been with us for a bit and joined in on some discussions, you will reach the magic number and these features will open up to you. (Note posts in the Village suburbs don't count toward your total!)
Sorry for any inconvenience, we all go through it! Nothing personal.
Sorry for any inconvenience, we all go through it! Nothing personal.
Visit my website, "The Paranormal DESTINATION"
Visit my website, "The Paranormal DESTINATION"
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text:
Maritime Vessels Directory
- Type
- Companies
Oil Production and Storage Unit | Flag: Bermuda | Port: HAMILTON
Oil Production and Storage Unit | Flag: Bermuda | Port: HAMILTON
Oil Production and Storage Unit | Flag: Bahamas | Port: NASSAU
Maritime News
Putting Palatka Back on the Map
Diverse and conveniently located, St. Johns Ship Building has quickly developed into a reliable partner for its many repeat customers. Today, and as a direct result, a lot more people know exactly where Palatka, Florida is located.On the St Johns River, just 60 miles south of Jacksonville, lies the sleepy town of Palatka, Florida. Founded as a trading post in 1821, its location on the highly navigable river made the area attractive to orange growers and timber men alike.In its heyday between 1875 and 1900, Palatka – "the gateway to Florida's interior" – was a tourist destination with several posh hotels having the capacity to host up to 6,000 guests.
Prepare Now for 40,000 Offshore Wind Jobs
The offshore wind industry in the United States is growing exponentially, with multiple projects in the development stages off of the Atlantic coast. The total megawatt capacity of U.S. offshore wind farms is anticipated to reach 22,000 by 2030 and 43,000 by 2050. To support this growth, U.S. Department of Energy reports estimate over 40,000 new jobs will be created by 2030.The new jobs anticipated to support the offshore wind industry include a wide range of types, including engineers, trade workers, surveyors, scientists, technicians, managers, and seafarers. Wind turbine technician has been one of the fastest growing occupations in the United States in recent years.
Exceptional Growth in LNG Trade, Says Awilco
The exceptional growth in LNG trade recorded in the first half of the 2019 continued in Q3, says Awilco LNG Group, the Norwegian based fully integrated pure play LNG transportation provider.According to Fearnleys LNG total LNG trade is up about 13 % in the first nine months of the year vs last year. In line with normal seasonal patterns gas prices inched upwards in Q3 but remained historically low due to increased production and muted demand in the Far East.Due to a relatively mild winter reducing gas demand for power generation and higher nuclear power generation in Japan and South Korea, LNG imports decreased by 8 and 9 % y-o-y Jan-Sept respectively
MRS '19 Wraps Up @ SUNY Maritime
"The decrease in state spending on higher education is what keeps me awake at night" is how RADM Michael Alfultis, President, SUNY Maritime College, neatly summarized the biggest challenge he faces as the leader of one of the U.S.' leading maritime universities. "With a small student body (about 1700), the numbers simply don't work," noting that while state funding 15 years ago covered two-thirds of the college's operating expenses, that percentage hovers at or below 30% today.The 10th Annual Maritime Risk Symposium closed yesterday at the Maritime College State University of New York feature a panel of three presidents of leading U.S.
Ulstein Debuts Zero-Emission Offshore Ship Design
Ulstein Group unveiled a hydrogen-powered ship design that it claims is market-ready, offering zero-emission marine operations.Recently, DNV GL identified the five most promising alternative fuels for shipping, with hydrogen as the ultimate zero-emission solution. The first complete hydrogen fueled prospect has been put together by Ulstein Design & Solutions BV and Nedstack fuel cell technology BV. The ULSTEIN SX190 Zero Emission DP2 construction support vessel is Ulstein's first hydrogen powered offshore vessel, featuring a Nedstack fuel cell power system. The DP2 vessel can cater for a large variety of offshore support operations.


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Full House Take 2
Title: 풀하우스 TAKE2 / Full House Take 2
Chinese Title: 浪漫满屋 2
Also known as: Full House 2
Genre: Romance, comedy
Episodes: 16 (2 parts in each episode)
Broadcast network: SBS Plus
Broadcast period: 2012-Oct-22 to 2012-Dec-13
Air time: Monday to Thursday 12:30 (1 part/day @ 35 minutes/part)
Related Series: Full House Series
This series pivots around a hapkido teacher Jang Man Ok (Hwang Jung Eum) becoming a stylist of top idol group TAKE ONE, composed of the perfectionist Lee Tae Ik (No Min Woo) and a free yet kind guy named Won Kang Hwi (Park Ki Woong) and getting into a romantic relationship with them.
Lee Tae Ik became an idol in order to gain back the house where he had lived with his late parents. Can Lee Tae Ik regain "Full House" ? And what about these three's future in love…?
Main Cast
No Min Woo as Lee Tae Ik
– Ahn Do Gyu as Lee Tae Ik (child)
– Oh Jae Moo as Lee Tae Ik (teen)
Hwang Jung Eum as Jang Man Ok / Jang Michelle
– Noh Jung Ui as Jang Man Ok (Child)
Park Ki Woong as Won Kang Hwi
– Jung Yoon Suk as Kang Hwi (child)
Yoo Seol Ah as Jin Se Ryuong
Supporting Cast
Kim Byung Se as Hwang Bum Soo
Lee Hoon as Lee Joon
Lee Seung Hyo as Bae Go Dong
Jung Ji Ah as Song Noh Ra
Heo Jae Ho as So Ji Sung
Kim Do Yun (1978) as Han Ga Ryun
Jang Hang Sun as Man Ok's grandfather
Oh Na Mi as stylist Choi
Yoo Tae Woong as Tae Ik's father
Kim Ye Ryung as Tae Ik's mother
Kuroda Fukumi as Tae Ik's aunt
Kang Doo as Sangsudong Wolf / Sang Dae
Han Yeo Wool as secretary
Ahn Yong Joon as Jay / Jung Chul
Lee Shin Ae (이신애) as Enterteinment news reporter
Song Min Hyung as President Director of U Ent.
Yang Han Yul (양한열) as hapkido student
Kim Tae Young (김태영) as Ophthalmologist
Lee Jung as radio program MC
Jo Jae Yoon as China's Korean taxi driver
Yang Han Yeol
Production Credits
Production Company: Kim Jong Hak Productions & Digital Khan
Chief Producer: Kim Yong Jin
Director: Kim Jin Young, Nam Ki Hoon
Original writing: Manhwa Full House by Won Soo Yeon
Screenwriter: Park Young Sook
– This drama is based on manhwa by writer Won Soo Yeon and was jointly produced by Korean, Chinese and Japanese companies and finished filming in April.
– This drama premiered in Japan on 2012-Oct-05 with Japanese Title 'フルハウスTAKE2' in TBS Channel 2.
Related Photo
(Other Photo from Official Site)


text:
How to Use
the Readings
Inquiry Question
Reading 4: The International Scene at Hyde Park
Franklin Roosevelt was the first modern president to use the media in a systematic manner in order to promote his ideas and to reach the public. Since the earliest years of his public career, Franklin Roosevelt had invited national political figures to lunch, tea, or dinner at his mother's home. Reporters were usually present at these very open events, much to Sara Roosevelt's dismay. She was a reluctant participant who disliked living in the public eye. Nonetheless, the Roosevelts continued to offer hospitality to members of the press, both at Springwood and also at Val-Kill, Eleanor Roosevelt's country retreat. The newspaper and radio reports about the President, his family, and the guests at their Hyde Park home were of great interest to the American people.
By 1939, Roosevelt and the nation's attention began moving from the crisis of Depression to a new crisis: global conflict. As the international situation became tense and war loomed, activities at Springwood assumed new significance to the world at large. Springwood soon became the staging area for a series of well-publicized international visits. These events began with the visit of King George VI and Queen Elizabeth of Great Britain in June of 1939. The royal couple was visiting the Province of Canada and the visit to Hyde Park was made to appear as casual as possible, as if they were just friends "dropping by" to visit.
In fact, the visit was designed to reshape American public opinion about the British royal family, making King George VI and Queen Elizabeth seem like a normal, likable couple. Britain was close to war with Germany and President Roosevelt knew he had to move a neutral, isolationist American public towards a pro-British stance. Roosevelt's strategy was a huge success. Major newspapers reported the royal visit in glowing terms and filled their pages with features and photos from cover to cover for an entire week and more.
When President Roosevelt delivered the annual address to Congress on January 6, 1941, he introduced his Lend-Lease plan and his idea for a better world to live in. This idea was presented as the Four Freedoms: freedom of speech and expression, freedom of worship, freedom from want, freedom from fear. Congress subsequently passed the Lend-Lease Act.
From then on, Franklin Roosevelt's formula for entertaining government officials and personalities from around the world in Hyde Park included a great deal of informality, casual get-togethers, sight-seeing, and plenty of publicity.
While working on Lend-Lease, Roosevelt formed a close partnership with Winston Churchill, and they met repeatedly at Springwood during the war years. The private, relaxed setting was conducive to productive meetings. During his visits, Churchill enjoyed Springwood's comforts and scenic view, rides through the wooded acres, and swimming parties at Val-Kill. Yet the two heads of state also accomplished a great deal, developing wartime military strategies, agenda topics for conferences with other Allies, and a practical vision of the post-war era.
Less than a year after the "Four Freedoms" speech, President Roosevelt grimly returned to Congress to announce the Japanese attack on Pearl Harbor, Hawaii on December 7, 1941, declaring it a "date which will live in infamy." Congress immediately declared war on Japan, Germany, and all nations in the Axis alliance.
Through the years of the Second World War, the Roosevelts continued to host royal families in exile and other international personalities at Springwood. Roosevelt enjoyed offering our democratic style of hospitality to his world visitors while demonstrating to the American people the hardship endured by many of the world's citizens.
When President Roosevelt finished meeting with Allied leaders at the Cairo and Teheran conferences in December 1943, he returned to Hyde Park. From his study in the Presidential Library next to his home, he presented a Christmas Eve report to the American people in the form of one of his familiar fireside chats. In doing so, he connected Springwood not only to himself but the nation at large:
But everywhere throughout the world--through this war that covers the world--there is a special spirit that has warmed our hearts since our earliest childhood--a spirit that brings us close to our homes, our families, our friends and neighbors--the Christmas spirit of "peace on earth, goodwill toward men." It is an unquenchable spirit.¹
Questions for Reading 4
1. How did Franklin Delano Roosevelt use entertaining at Springwood to advance his goals? Give some examples of his success with this approach.
2. In what ways did Springwood serve as an extension of the White House? Why did so many foreign leaders visit with Franklin Roosevelt at Hyde Park?
3. Publicity was essential in shaping public opinion. How did people learn about current events prior to the use of electricity? What types of media were available to Franklin Roosevelt? Which medium was Franklin Roosevelt the first president to use that allowed him to "visit" and speak directly to people in their homes?
Reading 4 was compiled from Russell Freedman, Franklin Delano Roosevelt (New York: Clarion Books, 1990); Buhite and Levy, eds., The Fireside Chats of Franklin D. Roosevelt (Norman: University of Oklahoma, 1992); and Olin Dows, Franklin Roosevelt at Hyde Park (New York: American Artists Group, Inc., 1949).¹Buhite and Levy, eds., The Fireside Chats of Franklin D. Roosevelt (Norman: University of Oklahoma, 1992), 274.


text:
Next Episode of Spraakmakende zaken is
In Spraakmakende Zaken Paul Rosenmöller receives his guests in 'City Pavilion' in a winter atmosphere in Amsterdam, where he talks with them on burning issues from the recent past.
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Sept. 20, 2008
Head coach Jerry Smith, on Cal Poly winning in overtime: "It was a confusing goal for a lot of people, as another player [for Cal Poly] was in an offsides position and the lines judge raised his flag so we stopped playing. We should have not stopped playing because the player who scored was not in an offsides position and it was the correct call."
Smith, on the team's performance: "I was very proud of the effort we put into the game, especially after we gave up the first goal. We played very well tonight; we just need to figure out how to prevent goals from going in because we are very good between the two penalty boxes."
Smith, on playing in the penalty box: "The ball is moving, our team is combining and we are keeping possession. We just are not scoring as much as we should and we are not preventing goals as much we should, both are penalty box issues."


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How private browsing works
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Incognito mode stops Chrome from saving your browsing activity.
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Chrome won't remember the files you download while browsing in private. But, they're still saved to your Downloads folder, even after you exit Incognito. You and anyone who uses your device can see and open the files.
All bookmarks you create are saved to Chrome.
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Incognito mode runs in a separate tab from your normal Chrome tabs.
If you have an Incognito tab open and you open another one, your private browsing session will continue in the new tab. To exit Incognito mode, close all Incognito tabs.
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Lemon Curd
I was so happy to find the following recipe for lemon curd, tested by the University of Georgia for the National Center for Home Food Preservation, but I was not so excited to prepare it because I don't often have bottled lemon juice on hand—it's not my favorite product. I've made lemon curd with Meyer lemons, and it is delicious, but Meyers aren't acidic enough to can safely, what with all that egg protein (I have made frozen Meyer lemon curd though, and it is delicious).
So as far as canning goes, I set the recipe aside. Then I read Linda Ziedrich's most recent post "Real Lemon versus ReaLemon," which pretty definitively establishes that real lemon juice can be substituted for bottled lemon juice in recipes, and I was re-inspired to make the curd. Her splendid blog, A Gardener's Table, is an excellent source for canners, both in terms of science, safety, and originality of recipes. (I highly recommend her books, too.) http://agardenerstable.com/2011/04/19/real-lemon-versus-realemon/
So here is the curd recipe from the NCHFP. I hate publishing a recipe that calls for a ton of egg yolks and then leave the reader stuck with all those extra whites, so following is a terrific little cake recipe that will use up most of those whites.
Lemon Curd
3 to 4 half-pint jars
21⁄2 cups sugar
1⁄2 cup lemon zest
1 cup lemon juice
3⁄4 cup unsalted butter, chilled, cut into small pieces
7 large egg yolks
4 large whole eggs
Have ready 4 clean half-pint canning jars and bands. Place new lids in a pot of simmering water to soften the rubberized flange
Fill boiling water canner with enough water to cover the filled jars by 1 to 2 inches. Use a thermometer to preheat the water to 180°F. Do not heat the water in the canner to more than 180°F before jars are added. If the water in the canner is too hot when jars are added, the process time will not be long enough. The time it takes for the canner to reach boiling after the jars are added is 25 to 30 minutes. Process time starts after the water in the canner comes to a full boil over the tops of the jars.
Combine the sugar and lemon zest in a small bowl, stir to mix, and set aside about 30 minutes.
Pre-measure the lemon juice and prepare the chilled butter pieces.
You will need a double boiler or pot that a metal bowl will fit on top of. Heat water in the bottom pan of a double boiler or pot to a gentle boil. The water should not boil vigorously or touch the bottom of the top double boiler pan or bowl in which the curd is to be cooked or the eggs will cook too fast.
Add the egg yolks and whole eggs together in the top of the double boiler or metal bowl on the counter, and whisk until thoroughly mixed. Slowly whisk in the sugar and zest, blending until well mixed and smooth. Blend in the lemon juice and then add the butter pieces to the mixture.
Place the top of the double boiler or metal bowl over the boiling water in the bottom pan. Stir gently but continuously with a cooking spoon, to prevent the mixture from sticking to the bottom of the pan. Continue cooking until the mixture reaches a temperature of 170 F. Use a food thermometer to monitor the temperature.
Remove the double boiler from the stove and place on the counter and continue to stir gently until the curd thickens (about 5 minutes). Strain curd through a mesh strainer into a glass or stainless steel bowl; discard the zest.
Fill hot strained curd into the clean, hot half-pint jars, leaving 1⁄2-inch headspace. Release any air bubbles by inserting a butter knife into the jar. Wipe rims of jars, place on the lids and screw on the bands fingertip tight.
Process the jars for 15 minutes, 20 minutes for up to 6,000 feet altitude, and 25 minutes for altitudes over 6,000 feet.
Allow the jars to cool, and then check the seals.
Store in a cool, dark place. Use the lemon curd within 3 to 4 months. (Over this time and browning or separation may occur. The curd should be discarded if this occurs.)
You can also freeze the curd. Pour the strained curd into freezer containers, and place in the refrigerator. When cool, place in the freezer. The curd will hold for 1 year. Thaw in the refrigerator.
Almond Torte with Poppy Seeds
Serves 8
In the search for desserts that use up extra egg whites, I found a version of this simple torte in The United Nations International School Cookbook. This recipe is best served fresh from the oven, as over time the cake will collapse. I haven't tested this recipe at altitude, but I imagine it will sink faster the higher you are. This adaptation was first published in Italian Family Dining (Rodale 2005).
6 large egg whites
1 cup granulated sugar
1 cup finely ground almonds
1/2 cup flour
8 tablespoons sweet butter, melted (1 stick)
2 teaspoons almond extract
1 1/2 teaspoons lemon zest
1 tablespoon poppy seeds
Preheat oven to 375F.
Grease a 10-inch cake pan. In a large bowl, beat the egg whites until they are light but not stiff then beat in the sugar. Stir in the remaining ingredients and mix well.
Pour the batter into the pan and bake for about 35 minutes, until a thin knife plunged into the center of the cake comes out clean.
Serve with powdered sugar or whipped cream.


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Pondering a cruise? There's an app for that. In fact, you'll find several you can use for planning, booking and enjoying cruises. Unless otherwise noted, all apps work on the iPhone, iPod touch and iPad (a few may also offer a specially designed version for iPad). BlackBerry and Android availability noted as applicable. Most are free or cost less than $5.
Before you cruise
Cruise Finder, by iCruise: This must-have app has itineraries for every major cruise line, searches for hot cruise deals and includes photos, deck plans, etc., for more than 220 cruise ships. Free
Cruise Finder, by Condé Nast Traveler: This app helps plan cruises but is less comprehensive than iCruise's. It does include a few lines Cruise Finder omits, and its Condé Nast Traveler articles and insider tips are pluses. Free
Berlitz Cruise Ships 2011: This touch-and-scroll version of Douglas Ward's book "Berlitz Complete Guide to Cruising & Cruise Ships" features reviews and ratings for 284 ships and recommendations for explorers, families, etc. It has fewer photos than either Cruise Finder app and no deck plans. $11.99
Ship Mate: Eight versions, each specific to Carnival, Celebrity, Costa Cruises, Holland America, MSC, Princess, Norwegian and Royal Caribbean. Ship Mate's strengths are its deck, itinerary and offshore excursion info. Both Cruise Finder apps are better for booking cruises. $1.99
Cruise Cam: Features cameras from almost 100 ships and 12 cruise lines and more than 150 port cams, letting you sample a cruise from afar. $1.99
While onboard
Cruise Card Control: Helps track bar tabs, fees for shore excursions, souvenir costs and other expenses. $1.99
Ship Finder: Tracks ship movements in real time. The paid version provides more details. It's fun tracking nearby ships. Free version and an upgraded $4.99 version.
Ships Ahoy!: Point the camera of your iPhone 4 or 3Gs at a ship to see its name and details. $2.99
TripAdvisor: Cruise forum offers discussions on cruise lines and itineraries, and reviews can help users arrange their own shore excursions. Also available for Android and BlackBerry. Free
Embarkation points
There are numerous apps for cities where cruises embark, stop in port or end. Search iTunes for "Los Angeles," "Miami," "New Orleans" or "New York City," and you'll have dozens of choices. Here are just a few of the free apps.
The Alaska App: Entertaining mobile version of Alaska.org can help you can locate a diversity of topics that include mountains, moose and mochas. Free
Miami: Guide to Miami lodging, dining, beaches, etc., from the Greater Miami Convention & Visitors Bureau. Free
iVisitLauderdale: Guide to hotels, dining, water activities, etc., for greater Fort Lauderdale, Fla. Free
Los Angeles Way: Comprehensive guide to dining, Wi-Fi, shopping, tours, etc. Free
New Orleans City Guide: Details architecture, culture, night life, the French Quarter and more. Available for Android and BlackBerry. Free
New York Way: Comprehensive guide to events, street eats, subways, etc. Free
Miscellaneous tools
Taxi Magic: Helps you find a taxi back to the ship if you wander ashore on your own. Available for Android and BlackBerry. Free.
Frommer's Travel Tools: Includes a time translator, tip calculator, city guides, virtual postcards and more. Free
Simply Postcards: Choose a photo and recipient and simplypostcards.net prints, stamps and mails your real postcard the next day. App and first postcard are free, then prices range from $1.99 each to $30 for 30.
Google Maps: For directions by car, foot or public transportation. It's my most essential app. Free.
Weather Channel app: Carrie Gonzalez of Cruise Critic says: "When you are in a different location every day, it's useful to keep a check on the weather." Available for Android and BlackBerry. Free.
Evernote: Helps you organize photos and keep track of where you saw what, etc. Available for Android and BlackBerry. Free.
XE Currency: App converts U.S. dollars to more than 180 world currencies. Available for Android and BlackBerry. Free.


text:
The UAB Department of Music Guest Artist Clarinet Recital will feature Buffet Clarinet artists Julia Heinen and Peter Wright, with pianist Maila Springfield at 7:30 p.m. Sept. 18 in UAB's Mary Culp Hulsey Recital Hall, 950 S. 13th St.
The recital will feature works by Torisi, JeanJean, Poulenc, Mendelssohn, Kovacs and Romero. Admission is free. Call 205-934-7376 for more information.


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Common Core Glossary
Achieve—An organization founded in 1996 by a group of governors and corporate leaders to work for standards-based education reform across the states. Achieve helped evaluate and promote the initial Common Core State Standards after they were drafted by the National Governors Association and the Council of Chief State School Officials.
CC—Common Core State Standards.
CCSSO—Council of Chief State School Officials, coauthored—with the National Governors Association—the Common Core State Standards.
Common Core—Common Core State Standards, released in 2010.
FERPA—Family Education Rights and Privacy Act, a federal law that protects the privacy of student educational records. In 2013, the U.S. Department of Education amended FERPA to allow any government or private entity that the Department says is evaluating an education program access to student's personally identifiable information without parental notification.
Gates Foundation—the Bill & Melinda Gates Foundation, a nonprofit that has provided millions of dollars in funding since 2007 to help develop and advance Common Core State Standards and student data systems.
inBloom—a nonprofit founded in 2012 by the Bill & Melinda Gates Foundation to build a $100 million database to track students from kindergarten through college.
NAEP—National Assessment of Education Progress, a federal program to provide a national "snapshot" of United States students' achievement at grades 4, 8, and 12. NAEP began holding national assessments in 1969 and continues through the present day.
NCLB—No Child Left Behind, a federal education initiative passed under the Bush Administration.
NGA—National Governors Association, coauthors—along with the Council of Chief State School Officials—of the Common Core State Standards.
P–20 longitudinal data system—preschool through workforce student tracking database.
PARCC—Partnership for Assessment of Readiness for College and Careers, a consortium of 26 members states that has received $170 million in federal education dollars to craft standardized assessments that align with the Common Core State Standards.
PISA—Programme for International Student Assessment.
SBAC—SMARTER Balanced Assessment Consortium, a group of 31 member states that has received $160 million from the U.S. Department of Education to develop standardized assessments that align with the Common Core State Standards.
RTTT—Race to the Top, a program which provided states an opportunity to compete for a share of $4.35 billion reserved for state education incentives by the American Recovery and Restoration Act.


text:
Stop the Cull
Stop the cull
Get the tune on iTunes here ► http://goo.gl/62fC68
SUBSCRIBE for more Weebl ► http://is.gd/MoreWeebl
Made with Brian May of Queen fame (He's pretty good on guitar you know) and the very loud, Brian Blessed of Flash Gordon and shouting fame. This is probably the most amazing thing I've ever been involved in and it's for a great cause too.
The UK Government want to kill badgers. Lots of them. I like badgers. I like Badger Badger Badgers. Of course I do, they're awesome. If you're in the UK then you can help stop this.
Visit Weebl's STORE ► http://is.gd/WeeblsStore
Follow Weebl on Twitter ► http://is.gd/TheWeebl
LIKE Weebl's Stuff on Facebook ► http://is.gd/WeeblFacebook
If you like what we're doing then check out our website for GAMES and MORE:
► http://weebls-stuff.com
WHAT IS WEEBL's STUFF?
Animations, sketches and songs by the Mr Weebl and the Weebl's Stuff Team.
You can also buy the music for the animations on iTunes, Amazon and Bandcamp.
If you like what you've watched then please subscribe.
Q: What do you use to animate?A: Mostly Flash and a bit of After Effects.
Q How do you make your music?A: Reason/Record by Propellerheads. Melodyne by Celemony. Cubase (rarely) by Steinberg. I also use Adobe Audition for voice editing and a SE2200a mic.


text:
Surgery for Ménière's disease can cause permanent damage to your hearing. Talk with your doctor about surgical options if repeated attempts at less invasive treatment methods have failed to relieve your symptoms.
The cause of
Ménière's disease is unknown, but it may be related to
a fluid imbalance in the inner ear. This fluid (endolymph) is
contained in a part of the inner ear called the endolymphatic sac. Two surgeries may be done:
In vestibular nerve section, the nerve that controls hearing and
balance on the affected side is identified. Then the balance portion of that
nerve is cut, leaving the part of the nerve that controls hearing intact. The part of the nerve that controls hearing is close to the part that controls
balance, so there is a risk of hearing loss in the affected ear.
During the recovery period, the brain adapts to the lack of input
from the ear that was operated on, and normal balance sense usually
returns. Other symptoms of Ménière's disease, such as tinnitus, hearing loss, and fullness in the ear, aren't helped by this surgery. You may need to stay on a low-sodium diet and take diuretics.
This procedure requires
general anesthesia and a hospital stay.
Labyrinthectomy removes the
balance center of the inner ear (labyrinth). This nearly always stops vertigo
but also results in total hearing loss in that ear. It is only used
for people who have already lost most of their hearing.
Last Revised:
April 12, 2012
Healthwise Staff
Medical Review:
Anne C. Poinier, MD - Internal Medicine & Barrie J. Hurwitz, MD - Neurology
This information does not replace the advice of a doctor. Healthwise, Incorporated disclaims any warranty or liability for your use of this information. Your use of this information means that you agree to the Terms of Use. How this information was developed to help you make better health decisions.
To learn more visit Healthwise.org
© 1995-2012 Healthwise, Incorporated. Healthwise, Healthwise for every health decision, and the Healthwise logo are trademarks of Healthwise, Incorporated.


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Security concerns over Australia's e-health records
- 23 April, 2012 11:34
As Australia grinds ever-closer to putting our health records online from (allegedly) 1 July, disturbing news is emerging. US hospitals are seeing more data breaches, and Australian medical experts warn that patient safety could be put at risk.
"It is not yet possible to make any definitive statement about whether the personally controlled electronic health record is safe or not," wrote three experts in the latest subscriber-only Medical Journal of Australia.
According to News-Medical.Net, the new e-health system has been subject to growing criticism based on privacy and security concerns, and that's down to the unreliable performance of the National E-Health Transition Authority (NEHTA).
There are "accusations of ineffective oversight and failure of administrators to acknowledge design flaws" and "warnings that the system will not succeed because its implementation has been ill-considered and rushed," according to the report — although NEHTA has pulled back the pace.
One of the critics is NEHTA's own chief clinical advisor, Dr Mukesh Haikerwal. His co-authors are Enrico Coiera, director of the University of NSW Centre for Health Informatics; and Michael Kidd, executive dean of Flinders University's Faculty of Health Sciences.
I hardly need to tell CSO Online readers that we're still seeing vast amounts of personal and financial data being lost. It's unacceptable. It needs to stop. But when it comes to medical data, the stakes are far higher.
Errors in readings could have life and death implications, Dr Haikerwal reported to have said. Quite.
The medicos' editorial calls for a national governance regime for e-health clinical safety generally, covering inaccuracies in data as well as security. But will that be enough?
CSO Online understands that industry concerns are less with the NEHTA core stack and more with medical practice management and other third-party software systems that interface with it, and with the quality of their implementation and operation in the more than 10,000 medical practices around the country.
AusCERT general manager Graham Ingram has previously raised concerns about the difficulty of securing end-users' computers.
In the financial sector we have security standards, the best-known of which is the Payment Card Industry Data Security Standard (PCI DSS). Yet investigators tell us that in more than 60 per cent of breaches there was a failure to meet that standard.
One particularly egregious US example was the Stratfor breach. The company didn't merely fail to meet PCI DSS compliance; they didn't even try — with credit card numbers stored unencrypted in a database with no password.
Did Stratfor suffer a penalty for this? As far as we know, no.
Indeed, as far as we know, no Australian organisation has lost its merchant facility for failing its PCI DSS compliance. And why would MasterCard, Visa and the rest cut off their revenue stream?
The rules for medical data are less rigorous. There's industry accreditation by organisations such as the Royal Australian College of General Practitioners, but their infosec standards are... aspirational.
CSO Online understands that GPs don't want to improve their infosec practices, but still want indemnity against data being lost on their watch unless it's proved wilful or negligent — and their staff to sign a code of conduct that covers them against any staff action that leads to data being lost.
Hang on.
Time to recalibrate, methinks.
How about we stop talking about organisations "losing" personal data like it's a little bit of a whoopsie. Let's call it as it is, neglecting to take proper responsibility for that data.
Note: I've deliberately chosen words with strong legal or ethical meaning. Negligence. Impropriety. Irresponsibility.
And while we're at it, let's make it a crime.
When I floated this idea on Twitter yesterday I got immediate support from Leslie Nassar, technology director at digital agency Amnesia Razorfish — although he was clearly speaking in a personal capacity.
"It's galling when Sony loses a massive cache of personal data without penalty, while lobbying for torrents to be criminalised," [[xref: https://twitter.com/#!/leslienassar/status/193900713678618625 |he tweeted|]].
"What are the real-world ramifications of tacitly giving criminals your personal data, versus watching a download of a FTA [free-to air television] show?" he asked.
We know the answer already. Just watch Bennett Arron's? You join the dots.
Yet right now an organisation that's negligent suffers no legal penalty. That's wrong, especially when the fixes are simply ignored.
The Australian Privacy Foundation would agree too.
"We've been laying off these organisations, permitting them to 'self-regulate', ha ha. It is simply inadequate," said Professor Roger Clarke, chair of the Australian Privacy Foundation, in the wake of the Apple iPhone location scandal and the Sony data breaches last year.
"The law has to get to grips with detail now. It's got to be technology-specific, and it's got to create teeth. We've got to have criminal offences for organisations that are insecure."
Agreed. It's time to put a bit of stick about...
Contact Stilgherrian at email@example.com or follow him on Twitter at @stilgherrian
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Traditional Hand Woven Rug 6'4 X 9'5
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Providing the highest quality and finest designs in Hand Made Rugs & Tapestries, from Contemporary,Traditional,European to Antique, plus the largest collection of Over & Unusual size rugs.
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