text:
|Publication number
|Publication type
|Application number
|Publication date
|Mar 12, 1996
|Filing date
|May 15, 1995
|Priority date
|Aug 17, 1993
|Fee status
|Publication number
|Patrick S.-L. Wong
|Original Assignee
|Alza Corporation
|Export Citation
|BiBTeX, EndNote, RefMan
|Patent Citations (23), Referenced by (43), Classifications (8), Legal Events (3)
|External Links: USPTO, USPTO Assignment, Espacenet
This application is a continuation of application Ser. No. 08/108,094, filed Aug. 17, 1993, now abandoned and benefit of the filing date of said earlier filed application is claimed under 35 U.S.C. � 120.
The present invention is related to the protracted pulsatile delivery of an active agent. More particularly, it is related to osmotically-activated devices for dispensing active agents to a biological environment of use for an extended or protracted period of time following an initial delay.
Osmotic dispensing devices for delivery of therapeutically active agents are well known in the art. Such devices use an expansion means to deliver an agent to an environment of use over a period of hours, days or months. The expansion means absorbs liquid, expands, and acts to drive out beneficial agent formulation from the interior of the device in a controlled, usually constant manner. The osmotic expansion means is used to controllably, usually relatively slowly, and over a period of time, deliver the agent. Thus, these devices are not generally used to delay the initial release of the agent.
The delay of the initial release of an agent has primarily been previously effected by coating the agent or a formulation containing the agent with a dissolvable or bioerodible coating layer, such as gelatin, which coating dissolves or erodes in the environment of use to then make the agent available. Delayed initial release has also been provided by dispersing the agent in a dissolvable or erodible matrix. However, such systems are often unreliable and release cannot be controlled with great accuracy due to the variability and relatively uncontrollable nature of erosion and dissolution.
Therefore, there remains a continuing need for improved methods and systems for providing a delayed initial delivery of an active agent to an environment of use that are reliable and that can be programmed to deliver the agent after a particular interval with increased accuracy. In addition, there is a need for systems which provide a protracted pulse delivery of an agent following a delayed startup, which delivery, once begun, can be extended and otherwise controlled.
The present invention is directed to a fluid-imbibing dispensing device for the extended or protracted delivery of an active agent following an initially delayed startup of the delivery to a fluid environment of use. The dispenser comprises a housing having a first wall section and a second wall section in reversibly sliding telescopic arrangement with each other, which housing maintains its integrity in the environment of use; an internal compartment surrounded and defined by the housing; at least one active agent formulation in a portion of the compartment defined by the first wall section; at least one opening in the side wall of the first wall section, each opening extending longitudinally along a portion of the side wall of the first wall section, for providing communication between the active agent formulation and the environment; expansion means within a portion of the compartment defined by the second wall section, for separating apart the first and second wall sections of the housing after exposure to the environment of use; and, optionally, a partition layer or push plate between the active agent formulation and the expansion means.
The invention also is directed to a method for delaying the initial delivery of an active agent to a fluid environment of use, after which delay the active agent is delivered to the environment over an extended period and in a protracted manner, the method comprising placing the dispensing device of the invention into the environment of use, allowing fluid to be imbibed through at least a portion of the housing of the dispensing device for causing the expansion means to expand and exert pressure on the slidably connected first and second wall sections to push apart and separate the two wall sections to deliver an active agent formulation through the opening or plurality of openings in the first wall section to the environment after an initially delayed period of time. That is, as the two wall sections are being pushed apart, an increasing area of the opening or openings becomes exposed to the fluid environment, allowing the active agent formulation to leach out of the device through the openings to provide a protracted pulse of agent delivery.
During the initial delay period in the environment, the volume of that portion of the compartment containing the active agent is kept constant; therefore, there is a negligible pressure gradient between the environment and the interior of the agent-containing compartment. As a result, net flow of the environmental fluid driven by the pressure to enter the agent-containing compartment is minimal, so that the active agent is not contaminated or diluted prior to commencement of delivery.
The drawings are not drawn to scale, but are set forth to illustrate various embodiments of the invention. Like numbers refer to like structures.
FIG. 1 is a cross-sectional view of one embodiment of the present invention, the device being in closed or prepared form prior to placement in the environment of use.
FIG. 2 is the device of FIG. 1 in operation after activation by placement in the environment of use, showing the device partially opened to release the active agent formulation to the environment.
FIG. 3 is an exterior side view of the device of FIG. 2.
The present invention provides a device which is useful for the initial delayed delivery of an active agent formulation to a fluid environment of use, the delivery of the agent formulation from the dispensing device, once begun, being continued over an extended period; that is, all of the agent is not released into the environment at one time. By "extended period of time" is meant a protracted time period such as for one hour, up to several hours, days, weeks or months.
As used herein, the terms "therapeutically effective" amount or rate refer to the amount or rate of the active agent needed to effect the desired therapeutic, often beneficial, result.
The dispensing devices of the invention find use, for example, in humans or other animals. The environment of use is a fluid environment and can comprise the stomach, the intestinal tract, or a body cavity such as the peritoneum or vagina. A single dispensing device or several dispensing devices can be administered to a subject during a therapeutic program.
FIG. 1 depicts in cross-sectional view a presently preferred embodiment of the delivery device according to the present invention. The device is shown in closed or prepared form prior to placement in the environment of use. Dispensing device 1 comprises a housing 12 formed of a first wall section 14 and a second wall section 16. First wall section 14 and second wall section 16 are in reversibly sliding telescopic arrangement with each other. Housing 12 surrounds and defines an internal compartment 18. First wall section 14 surrounds that portion of internal compartment 18 that contains an active agent formulation 20 (not shown in FIG. 1). Second wall section 16 surrounds that portion of internal compartment 18 that contains an expansion means 22 for expanding and for occupying space in compartment 18. Second wall section 16 also contains a partition layer or push plate 24, which push plate 24 is positioned between the agent formulation 20 and the expansion means 22. Push plate 24, in a presently preferred embodiment, comprises a composition that is substantially impermeable to the passage of fluid, and it serves to restrict the passage of fluid present in the expansion means into that area of compartment 18 that contains the agent formulation. It operates to essentially maintain the integrity of the active agent formulation and the expansion means layer. Additionally, and importantly, push plate 24 acts to insure that the expanding driving force generated by the expansion means 22 is applied directly against the first wall section 14 to effect the separation of the two wall sections. Thus, push plate 24 must be of sufficient strength, thickness and rigidity to transfer the driving force against first wall section 14.
Each of first wall section 14 and second wall section 16 has an open end, the open end of first wall section 14 being adapted to fit within the open end of second wall section 16. The two wall sections at their open ends are close in size and they form a friction fit therebetween. The friction generated is sufficient to maintain the two wall sections together prior to activation of the expansion means but not so great as to keep the two wall sections from sliding apart once an expanding driving force is exerted. Where additional friction is desired, protrusions may be present at or near the open end of the first wall section for providing further friction between the two wall sections. First wall section 14 and second wall section 16 can be telescoped completely into a closed external walled position. The bottom edge of the open end of first wall section 14 provides a platform or ridge 28 protruding into compartment 18. Ridge 28 is adapted to receive the driving force of the expansion means 22, via the push plate 24, to effect the separation of the two wall sections.
First wall section 14 has a plurality of openings 30, shown in device 1 as four elongated openings 30a, 3Ob, 30c and 30d, which extend longitudinally along a portion of the side wall of the first wall section. According to the invention, the number of openings is variable, and may be selected from, generally, one to ten openings, or more, to moderate the rate of leaching of agent from the device. In a presently preferred embodiment, the number of openings 30 is from two to ten, depending on the protraction of release that is desired. The openings can have any shape, but in a preferred embodiment the shape is an elongated rectangle or ellipse. Alternatively, each opening 30 may consist of a series of smaller openings, such as for example squares, circles, triangles, rectangles or ellipses, extending longitudinally along the side wall of the first wall section 14.
In operation, as the expansion means 22 absorbs and imbibes fluid through second wall section 16 from the environment of use, it expands and pushes against push plate 24, causing the push plate to slide inside compartment 18. Push plate 24 moves toward and contacts ridge 28, pushing against ridge 28 and thus against first wall section 14 to cause the first wall section to slide apart from second wall section 16 as the expansion means 22 continues to expand. As the two wall sections are pushed apart, the openings 30 begin to become progressively exposed to the environment, causing the active agent formulation 20 to be exposed and released to the environment of use via the exposed portions of the openings 30, as illustrated in FIGS. 2 and 3.
FIGS. 2 and 3 illustrate the dispensing device 1 of FIG. 1 in operation after activation of the device by placement in the environment of use. FIGS. 2 and 3 show device 1 partially opened to release a portion of the active agent formulation 20 to the environment (FIG. 2 as a longitudinal cross-sectional view and FIG. 3 as a longitudinal exterior view). As illustrated in FIG. 2, first wall section 14 has been partially separated from second wall section 16 to expose a portion of the openings 30, separation having occurred by the expanding driving force of the expansion means 22, which has expanded in size as a result of imbibing fluid from the environment. The arrows in FIG. 2 indicate the exiting of the active agent formulation 20 from internal compartment 18 through the exposed portions of the openings 30 in first wall section 14, which are now in communication with the environment.
The delivery profile of the active agent from the device of the present invention can be determined by varying the characteristics of the openings 30, such as by varying the number, size and/or placement of the openings. For example, the time period for the initial delay of startup of delivery can be set by the initial distance of the openings from the open end of the second wall section 16, the initial distance illustrated as distance 32 in FIG. 1. The amount of active agent released over time can be determined by the length of the openings, by the number of openings present in the wall, by the width of the openings, or by a combination of these.
First wall section 14 may comprise a composition that is semipermeable, that is, it is permeable to fluid but impermeable to active agent and other ingredients contained in dispensing device 1, or it may, alternatively, comprise a composition that is impermeable to the exchange of fluid, agent and other ingredients. When an active agent or an active agent dosage form is sensitive to fluid from an exterior fluid present in the environment of use, it is preferred that first wall section 14 be substantially impermeable to the ingress of the external fluid to serve as a means for substantially protecting the agent or dosage form.
Because expansion means 22 operates by the imbibition of external fluid, second wall section 16 in at least a portion that is initially adjacent to expansion means 22 must be semipermeable; that is, it is permeable to the passage of fluid while being substantially impermeable to the passage of other ingredients contained in dispensing device 1. In one embodiment, second wall section 16 is semipermeable in its entirety. In another embodiment, second wall section 16 is composed of an impermeable material in that portion that initially contacts the openings 30, in order to protect the active agent from exposure to fluid from the fluid environment until such time as openings 30 themselves are exposed to the environment.
Wall sections 14 and 16 optionally comprise additional ingredients such as, for example, a plasticizer. Impermeable and semipermeable compositions suitable for use in wall sections 14 or 16, as well as suitable additives, are known in the art, examples of which are disclosed in U.S. Pat. No. 4,874,388, the entire disclosure of which is incorporated herein by reference.
Housing 12, comprising wall sections 14 and 16, is nontoxic, biologically inert, nonallergenic and nonirritating to body tissue, and it maintains its physical and chemical integrity; that is, housing 12 does not erode or degrade in the environment of use during the dispensing period. It is within the scope of the invention that the housing be insoluble only during the period of intended use and can thereafter dissolve away in the environment of the device. Thus, a dispenser is here contemplated which is unaffected by its environment, solubility-wise, at the situs of use or which, alternatively, is only slightly soluble during the period of intended use, such that once its active agent content has been removed it will then dissolve or erode away leaving no objectionable residue or empty container at the situs of use.
The expansion means or expandable driving means 22, operable for separating the first and second wall sections to release the active agent from the dispensing device of the invention, is nontoxic, nonallergenic and biologically inert. Expansion means 22 comprises, in one presently preferred embodiment, an osmopolymer. The osmopolymers interact with water and aqueous biological fluids and swell or expand to an equilibrium state. The osmopolymers exhibit the ability to swell in fluid and to retain a significant portion of the imbibed and absorbed fluid within the polymer structure. The expansion means 22 in another preferred embodiment comprises an osmagent. The osmagents are known also as osmotically effective solutes and they are also known as osmotically effective compounds. The osmagents that can be used for the purpose of this invention include inorganic and organic compounds that exhibit an osmotic pressure gradient across a semipermeable, i.e. a fluid-permeable, wall. The expansion means 22 in yet another preferred embodiment comprises an osmagent dispersed within an osmopolymer. The expansion means 22 can comprise a tablet or a layer, or a plurality of tablets or layers, or it can be pressed into second wall section 16. The osmagent or osmopolymer can be in any suitable form such as particles, crystals, pellets, granules, and the like, when pressed into a tablet layer and into wall section 16. Osmagents and osmopolymers are known to the art and are described in, for example, U.S. Pat. Nos. 3,865,108, 4,002,173, 4,207,893, 4,327,725 and 4,612,008.
Push plate 24, present in certain embodiments of the invention between the active agent formulation and the expansion means, is a means for transmitting the force generated by the expansion means against the first wall section 14, for maintaining the separate identity of the active agent formulation and the expansion means, and for substantially restricting the passage of fluid between the active agent formulation and the expansion means. Representative materials useful as a partition layer or push plate 24 are known to the art in, for example, U.S. Pat. No. 4,874,388.
The term "active agent formulation", as used herein, comprises the active agent to be delivered, as a liquid, solid, semisolid or thermosensitive composition, generally in a carrier substance and with or without additional inert ingredients. The term may additionally include dosage forms comprising the active agent which are capable of maintaining their physical configuration and chemical integrity while housed within the dispenser. These include, without limitation, tablets with or without a density element; matrix tablets; spheres; tiny pills; pellets and elongated tablets; capsules; elementary osmotic pumps, such as those described in U.S. Pat. No. 3,845,770; miniosmotic pumps, such as those described in U.S. Pat. Nos. 3,995,631, 4,034,756 and 4,111,202; and multichamber osmotic systems referred to as push-pull and push-melt osmotic pumps, such as those described in U.S. Pat. Nos. 4,320,759 and 4,449,983; all the above patents of which are incorporated herein by reference.
The pharmaceutically acceptable carrier useful herein may comprise more than one ingredient, such as, for example, a buffer, a viscosity regulating vehicle, a surfactant, dyes, a permeation enhancer, proteinase inhibitors, or other formulation ingredients and additives, as are known in the art. The carrier may contain more than one active agent. The active agent formulation can erode or disintegrate and can be in the form of a wax formulation, solid core or tablet, for example. The formulation can immediately dissolve upon exposure to fluid or it may erode slowly with or without the presence of excipients for controlling erosion.
The active agent formulation can be designed in a multitude of ways to provide a specific drug delivery profile. One embodiment may comprise a formulation that contains a biologically acceptable solid surfactant which is capable of slow dispersion in the environmental fluid. In another embodiment, the formulation may contain a fluid-insoluble wax and a surfactant so that the formulation is susceptable to erosion in the environment. In still another embodiment, the formulation may be effervescent and provide drug delivery in a finely dispersed form. This is accomplished by the addition of a solid basic compound capable of evolving carbon dioxide in the presence of an acid in the environment of use. Suitable basic compounds are disclosed in U.S. Pat. No. 4,265,874. In a further embodiment, the formulation may include an osmotic agent or solute, such as those described above with reference to the expansion means 22, so that when the formulation comes into contact with the environmental fluid, it immediately dissolves. In yet another embodiment, the agent formulation can be comprised of an agent and a thermoresponsive composition. In this manner, the formulation would exhibit solid-like properties at room temperature of 21� C. and within a few degrees Celsius thereof, and would have a melting point that approximates mammalian body temperatures of 37� C. and within a few degrees Celsius thereof. The term "thermoresponsive" as used herein in a preferred embodiment denotes the physical-chemical property of an agent carrier composition to exhibit solid, or solid-like properties at temperatures up to 31� C and become fluid, semisolid or viscous when disturbed by heat at temperatures from 31� C., usually in the range of 31� C. to 45� C. Suitable materials useful as active agent carriers and excipients are known in the art and are disclosed in U.S. Pat. Nos. 4,595,583 and 4,874,388, for example.
The terms "active agent" and "drug" are used interchangeably herein and refer to an agent, drug, compound, composition of matter or mixture thereof which provides some therapeutic, often beneficial, effect. This includes pesticides, herbicides, germicides, biocides, algicides, rodenticides, fungicides, insecticides, antioxidants, plant growth promoters, plant growth inhibitors, preservatives, antipreservatives, disinfectants, sterilization agents, catalysts, chemical reactants, fermentation agents, foods, food supplements, nutrients, cosmetics, drugs, vitamins, sex sterilants, fertility inhibitors, fertility promoters, microorganism attenuators and other agents that benefit the environment of use. As used herein, the terms further include any physiologically or pharmacologically active substance that produces a localized or systemic effect or effects in animals, including warm blooded mammals, humans and primates; avians; domestic household or farm animals such as cats, dogs, sheep, goats, cattle, horses and pigs; laboratory animals such as mice, rats and guinea pigs; fish; reptiles; zoo and wild animals; and the like. The active drug that can be delivered includes inorganic and organic compounds, including, without limitation, drugs which act on the peripheral nerves, adrenergic receptors, cholinergic receptors, the skeletal muscles, the cardiovascular system, smooth muscles, the blood circulatory system, synoptic sites, neuroeffector junctional sites, endocrine and hormone systems, the immunological system, the reproductive system, the skeletal system, autocoid systems, the alimentary and excretory systems, the histamine system and the central nervous system. Suitable agents may be selected from, for example, proteins, enzymes, hormones, polynucleotides, nucleoproteins, polysaccharides, glycoproteins, lipoproteins, polypeptides, steroids, hypnotics and sedatives, psychic energizers, tranquilizers, anticonvulsants, muscle relaxants, antiparkinson agents, analgesics, antiinflammatories, local anesthetics, muscle contractants, antimicrobials, antimalarials, hormonal agents including contraceptives, sympathomimetrics, polypeptides and proteins capable of eliciting physiological effects, diuretics, lipid regulating agents, antiandrogenic agents, antiparasitics, neoplastics, antineoplastics, hypoglycemics, nutritional agents and supplements, growth supplements, fats, ophthalmics, antienteritis agents, electrolytes and diagnostic agents.
Examples of beneficial agents which this invention can be utilized with are prochlorperazine edisylate, ferrous sulfate, aminocaproic acid, mecaxylamine hydrochloride, procainamide hydrochloride, amphetamine sulfate, methamphetamine hydrochloride, benzphetamine hydrochloride, isoproteronol sulfate, phenmetrazine hydrochloride, bethanechol chloride, methacholine chloride, pilocarpine hydrochloride, atropine sulfate, scopolamine bromide, isopropamide iodide, tridihexethyl chloride, phenformin hydrochloride, methylphenidate hydrochloride, theophylline cholinate, cephalexin hydrochloride, diphenidol, meclizine hydrochloride, prochlorperazine maleate, phenoxybenzamine, thiethylperazine maleate, anisindone, diphenadione erythrityl tetranitrate, digoxin, isoflurophate, acetazolamide, methazolamide, bendroflumethiazide, chlorpropamide, tolazamide, chlormadinone acetate, phenaglycodol, allopurinol, aluminum aspirin, methotrexate, acetyl sulfisoxazole, erythromycin, hydrocortisone, hydrocorticosterone acetate, cortisone acetate, dexamethasone and its derivatives such as betamethasone, triamcinolone, methyltestosterone, 17-β-estradiol, ethinyl estradiol, ethinyl estradiol 3-methyl ether, pednisolone, 17-β-hydroxyprogesterone acetate, 19-nor-progesterone, norgestrel, norethindrone, norethisterone, norethiederone, progesterone, norgesterone, norethynodrel, ST-1435, gestodene, aspirin, indomethacin, naproxen, fenoprofen, sulindac, indoprofen, nitroglycerin, isosorbide dinitrate, propranolol, timolol, atenolol, alprenolol, cimetidine, clonidine, imipramine, levodopa, chlorpromazine, methyldopa, dihydroxyphenylalanine, theophylline, calcium gluconate, ketoprofen, ibuprofen, cephalexin, erythromycin, haloperidol, zomepirac, ferrous lactate, vincamine, diazepam, phenoxybenzamine, diltiazem, milrinone, mandol, quanbenz, hydrochlorothiazide, ranitidine, flurbiprofen, fenbufen, fluprofen, tolmetin, alclofenac, mefenamic, flufenamic, difuninal, nimodipine, nitrendipine, nisoldipine, nicardipine, felodipine, lidoflazine, tiapamil, gallopamil, amlodipine, mioflazine, lisinolpril, enalapril, enalaprilat, captopril, ramipril, endlapriat, famotidine, nizatidine, sucralfate, etintidine, tetratolol, minoxidil, chlordiazepoxide, diazepam, amitriptylin, and imipramine. Further examples are proteins and peptides which include, but are not limited to, insulin, colchicine, glucagon, thyroid stimulating hormone, parathyroid and pituitary hormones, calcitonin, renin, prolactin, corticotrophin, thyrotropic hoemone, follicle stimulating hormone, chorionic gonadotropin, gonadotropin releasing hormone, bovine somatotropin, porcine somatotropin, oxytocin, vasopressin, prolactin, somatostatin, lypressin, pancreozymin, luteinizing hormone, LHRH, interferons, interleukins, growth hormones such as human growth hormone, bovine growth hormone and porcine growth hormone, fertility inhibitors such as the prostaglandins, fertility promoters, growth factors, and human pancreas hormone releasing factor.
It is to be understood that more than one active agent may be incorporated into the active agent formulation in a device of this invention, and that the use of the term "agent" or "drug" in no way excludes the use of two or more such agents or drugs.
The agents can be in a wide variety of chemical and physical forms, such as uncharged molecules, components of molecular complexes or nonirritating, pharmacologically acceptable salts. Also, simple derivatives of the agents (such as ethers, esters, amides, etc.) which are easily hydrolyzed by body pH, enzymes, etc., can be employed.
The amount of active agent employed in the delivery device will be that amount necessary to deliver a therapeutically effective amount of the agent to achieve the desired result at the site of delivery. In practice, this will vary widely depending upon the particular agent, the site of delivery, the severity of the condition, and the desired therapeutic effect. Thus, it is not practical to define a particular range for the therapeutically effective amount of active agent incorporated into the device.
For proper delivery of the active agent, it may be desirable in some instances for the dispensing device to deliver active agent to a particular environment of use. Thus, it may be necessary for the device to remain in a particular environment of use until such time as the agent formulation has been delivered or, alternatively, for the device to pass through one particular environment to another prior to delivering agent formulation. In such cases, additional elements are included in the device, or the device is designed in such a way to provide for such particular delivery. For example, when the environment of use is the rumen of a ruminant animal, a density element may be included in the dispensing device so that the device is weighted to remain within the rumen during the dispensing period. Density elements are known in the art and are discussed in, for example, U.S. Pat. No. 4,874,388. When the environment of use is the human stomach, it may be desirable for the device to, for example, have a low initial density or to include air in that portion of the internal compartment of the device that also contains the agent formulation. In this manner, the device will float on the surface of the stomach contents and remain in the stomach until the device opens to release the formulation. Where it is desirable, on the other hand, to delay the release of an active agent which, for example, is inactivated by the stomach contents or may cause nausea or bleeding by irritating the gastric mucosa so that delivery in the stomach is not desired, an enteric coating can be applied over at least that portion of the housing of the dispensing device that is comprised of a semipermeable membrane. Enteric coatings will remain intact in the stomach but will rapidly dissolve once they arrive at the small intestine, thereafter allowing fluid to be imbibed to activate the dispensing device. Enteric coatings are well known in the art and are discussed at, for example, "Remington's Pharmaceutical Sciences", Mack Publishing Co., Easton, Pa.
The total delay time prior to separation of the dispensing device and delivery of the active agent formulation can be controlled by a number of means. The effects of the design and placement of the openings in the first wall section of the device have been discussed previously herein. Additionally, for example, the rate of fluid imbibition into the expansion means can be controlled by the particular choice of semipermeable membrane. The rate of expansion of the expansion means can be controlled by the choice of composition of the expansion means. The distance of overlap between the open end portions of the first and second wall sections can determine the period of time required for the two sections to separate. Combinations. of such means may be used. Such control means are known in the art and can be determined without undue experimentation.
The devices of the present invention may be prepared by methods known in the art. For example, the first and second wall sections may be prepared by injection-molding or extrusion, for example, of the appropriate wall-forming materials into the desired shapes. Alternatively, one or both of the sections may be prepared by coating a substrate, such as a gelatin capsule or a portion thereof, with the wall-forming materials. The openings in the side wall of the first wall section may be formed during manufacture of the wall section, as by injection-molding or extrusion, or they may be formed after manufacture, by laser-drilling, cutting, punching, and the like. The osmotic expansion means may be separately prepared as a tablet and the tablet placed into the second wall section at the time of assembly of the device, or the osmotic material as particles, granules and the like may be pressed into the second wall section.
The device may be assembled in any number of ways, as can be determined without undue experimentation. For example, the first and second wall sections are formed to the desired shapes, after which the osmotic expansion means is placed in the bottom of the second wall section and a partition layer or push plate, if included, is placed above the expansion means. The active agent formulation is placed into the first wall section, and the open end of the first wall section is then positioned inside the open end of the second wall section and the two sections are compressed until they fit together tightly.
The above description has been given for ease of understanding only. No unnecessary limitations should be understood therefrom, as modifications will be obvious to those skilled in the art.
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|Nov 3, 2011
|Mar 11, 2014
|Flugen, Inc.
|Wearable drug delivery device having spring drive and sliding actuation mechanism
|Dec 16, 2010
|Aug 26, 2014
|Mcneil-Ppc, Inc.
|Rapidly disintegrating gelatinous coated tablets
|Feb 26, 2013
|Sep 22, 2015
|SinuSys Corporation
|Devices and methods for dilating a paranasal sinus opening and for treating sinusitis
|Jul 18, 2014
|Oct 6, 2015
|Johnson & Johnson Consumer Inc.
|Rapidly disintegrating gelatinous coated tablets
|May 20, 2013
|Oct 6, 2015
|SinuSys Corporation
|Devices and methods for dilating a paranasal sinus opening and for treating sinusitis
|Sep 10, 2010
|Jan 19, 2016
|Medipacs, Inc.
|Low profile actuator and improved method of caregiver controlled administration of therapeutics
|Dec 16, 2002
|Sep 11, 2003
|Midha Kamal K.
|Method for preventing abuse of methylphenidate
|Mar 12, 2002
|Sep 18, 2003
|Fernando Anzellini
|Thrombust; implantable delivery system sensible to self diagnosis of acute myocardial infarction for thrombolysis in the first minutes of chest pain
|Apr 28, 2003
|Oct 16, 2003
|Midha Kamal K.
|Pharmaceutical dosage form for pulsatile delivery of methylphenidate
|Jun 4, 2004
|Dec 16, 2004
|Sowden Harry S.
|Immediate release dosage form comprising shell having openings therein
|Aug 4, 2004
|Mar 10, 2005
|Coppeta Jonathan R.
|Methods for accelerated release of material from a reservoir device
|Jan 13, 2004
|Jul 14, 2005
|Rinker Roger A.
|Rapidly disintegrating gelatinous coated tablets
|Aug 4, 2005
|Mar 16, 2006
|Wong Patrick S
|Controlled release nanoparticle active agent formulation dosage forms and methods
|Jan 6, 2006
|Jul 20, 2006
|Boehringer Lngelheim Pharma Gmbh & Co. Kg
|Two-part capsule with pre-closure for housing pharmaceutical preparations for powder inhalers
|Dec 5, 2005
|Jun 7, 2007
|Smith Mark A
|Form fill and seal container
|Jan 8, 2008
|Jul 3, 2008
|Dieter Hochrainer
|Two-part capsule to accept pharmaceutical preparations for powder inhalers
|Jul 19, 2006
|Aug 27, 2009
|Franklin Amie E
|Improved pharmacokinetic profile of beta-adrenergic inverse agonists for the treatment of pulmonary airway diseases
|Oct 22, 2009
|Nickel Janice H
|Passive Cooling In Response To Ambient Environmental Properties
|Dec 3, 2008
|Oct 21, 2010
|Mark Banister
|Fluid metering device
|Apr 14, 2011
|Rinker Roger A
|Rapidly disintegrating gelatinous coated tablets
|Jul 14, 2011
|Ratio, Inc.
|Microneedle component assembly for drug delivery device
|Jul 14, 2011
|Ratio, Inc.
|Drug delivery device including tissue support structure
|Jul 14, 2011
|Ratio, Inc.
|Wearable drug delivery device including integrated pumping and activation elements
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|Optinose AS
|Nasal delivery device
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|Astute Medical Inc
|Methods and compositions for diagnosis and prognosis of renal injury and renal failure
|Dec 13, 2000
|Jun 28, 2001
|Alza Corporation
|Valve for osmotic devices
|Dec 13, 2000
|Jan 3, 2002
|Alza Corp
|Valve for osmotic devices
|U.S. Classification
|604/892.1, 424/472, 424/453, 424/473
|International Classification
|Cooperative Classification
|European Classification
|Sep 10, 1999
|Fee payment
Year of fee payment: 4
|Aug 26, 2003
|Fee payment
Year of fee payment: 8
|Aug 29, 2007
|Fee payment
Year of fee payment: 12


text:
Find out who's guest starring on Odd Mom Out this season and get the scoop on Goodwin's new babe!
Learn about Jewish summer camps nationwide that welcome interfaith families.
This booklet is a guide through the why and how of bringing Shabbat to your home and table. It includes all the blessings traditionally said at the table with candles, wine and the braided bread called challah.
Connecting Interfaith Families to Jewish Life in Greater Cleveland by providing programs and opportunities for interfaith families to experience Judaism in a variety of venues, meet other interfaith families, and to connect to other Jewish organizations that may serve their needs.
An interactive, fun and low-key workshop for interfaith/intercultural couples to talk about how to make major decisions together as they relate to raising a child.
Supporting rabbis and cantors looking to engage interfaith couples and families in their communities and help them make a stronger connection with Judaism.
A great way for Jewish professionals and volunteers who work with and provide programming for people in interfaith relationships to locate resources and trainings to build more welcome into their Jewish communities; connect with and learn from each other; and publicize and enhance their programs and services.
This blog is written by IFF staff and ranges from reactions to news, personal opinions and resources or guides for couples, families or program providers.
See all interested members (1)Add to my events
Join us for a moving evening...
Led by the Synagogue's dear friend, Mark Schonfeld
Saturday, July 28th. Service at 8:00 PM
All are welcome. Join us as we read Lamentations -- in Hebrew & in English: Poems & reflections with philosophical, emotional & intellectual messages commemorating the destruction of the Temple
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subset: commoncrawl


text:
Lyrics Depot is your source of lyrics to Baby on the plane by Lisa Germano. Please check back for more Lisa Germano lyrics.
Baby on the plane Lyrics
Artist: Lisa Germano
Album: Excerpts From a Love Circus
I see your eyes looking at me
Oh yeah, all right, love has started to take
You have given
I have taken a picture
This might not last forever
Your eyes beauty, and tequila
These eyes give this a reason
Baby on the plane
Woman shaking beside her
Oh yeah, your eyes, and tequila
Get me through today
Baby on the plane,
The woman next to her was so old
And she was shaking
Why do we go through this
'Cause of the way you look at me
Lisa Germano Lyrics
Lisa Germano Excerpts From a Love Circus Lyrics
More Lisa Germano Music Lyrics:
Lisa Germano - Cry baby Lyrics
Lisa Germano - Everyone's victim Lyrics
Lisa Germano - Guillotine Lyrics
Lisa Germano - Hangin' with a deadman Lyrics
Lisa Germano - OP8 ( Instrumental ) Lyrics
Lisa Germano - The devil loves L.A. Lyrics
Lisa Germano - Victoria's Secret "Just A Bad Dream" Lyrics


text:
Hackensack, NJUSA
Hometown: New York City
February 8, 2010
Photographer/Graphic/Fine artist from Hackensack, NJ. I do my own retouching and look to learn new things and network for ideas, locations, models and general technical aspects of creating images. http://MattWallac... "It's all about the Image"
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The anniversary of a natural disaster or terrorist attack can serve as a powerful reminder of earlier reactions to the tragedy, and can trigger renewed feelings of anxiety, sorrow, and concerns about the future. These reactions even after 10 years can interfere with daily functioning at home, work, or school.The National Child Traumatic Stress Network (NCTSN) has compiled resources for disaster response workers, educators, families, medical personnel, mental health professionals, and youth to help with recurring reactions and with current stresses and adversities.
In support of National Preparedness Month―sponsored by the U.S.
In order to bring greater awareness to the issue of posttraumatic stress disorder (PTSD), the United States Senate designated June 27th as National PTSD Awareness Day. In addition, June has been designated as PTSD Awareness Month by the National Center for PTSD (NCPTSD).
LGBT youth are routinely harassed because of their sexual orientation.
The NCTSN invites you to join us in observing World Refugee Awareness Month and, on June 20th, World Refugee Awareness Day. In doing so, we focus on the millions of refugees who live around the globe, recognizing their plight as well as their valuable contributions to our communities.
As a part of Mental Health Awareness Month, the National Child Traumatic Stress Network (NCTSN) invites you to join us in celebrating the 11th annual Children's Mental Health Awareness Day on May 5, 2016. Sponsored by the Substance Abuse and Mental Health Services Administration (SAMHSA), a division of the U.S.
In 2014 there were an estimated 415,129 children in foster care (Adoption and Foster Care Analysis and Reporting System). A child can be removed from the home and placed in foster care for a variety of reasons including abuse or neglect, parent-child conflict, and the presence of serious physical or behavioral problems in the child that cannot be addressed in the home.
Many youth who are identified (by themselves or by others) as lesbian, gay, bisexual, transgender, or questioning (LGBTQ) are routinely subjected to name-calling, bullying, and other forms of harassment. And even LGBTQ allies may be victimized. Underlying these behaviors can be discrimination and hate—which sometimes leads to violence.
Sexual violence—including child sexual abuse—crosses all ages, genders, races, ethnicities, and economic backgrounds. According to the Child Maltreatment 2014 report from the U.S.
April is the Month of the Military Child. This awareness month was established to underscore the important role children play in the Armed Forces community. There are approximately 2 million military children, ranging in ages from newborn to 18 years old; 1.3 million military children are school-aged. Care of military children sustains our fighting force, and strengthens the health, security, and safety of our nation's families and communities.


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New Doc Reveals the Tyranny of Political Correctness and Censorship Culture at Brown (heatst.com)
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The Original Hipster Of Hoboken!
Today is Election Day in Hoboken. Don't forget to vote.Click Here to learn more about the Original Hipster, Jim Doyle.
1. Jim was into nature before hipsters called it organic
Since its inception in 2004, Jim has been a member of the Hoboken Parks Organization along with his wife, Leah Healey, which has effectively advocated for the acquisition and creation of much needed parks in Hoboken, such as the newly opened 1600 Park (at the City's northern end), a park which HPO was instrumental in creating.
2. Jim knew how to party before hipsters did and he created his own 'social' club to prove it
Consistent with the Master Plan, Jim encourages steps to foster the creation of commercial, back office, and incubator businesses in future development of the City. That also include consideration for the preservation and rehabilitation of existing buildings to preserve our heritage and provide flexible spaces for small businesses and artisanal uses.
3. Jim was riding two-speeds before hipsters called them "fixies"
Among many great accomplishments, Jim helped launch the first bike share program in Hoboken. He's also actively involved in raising money for children at a special needs bike camp, Losing the Training Wheels.
4. Jim was burying throttle on a two-stroke way before hipsters were off tricycles
5. Jim drank Bud Heavy before hipsters drank PBR
Jim advocates that the City conduct a "Build Out Analysis" to examine existing zoning and the Master Plan to forecast what the City will become it is developed as currently allowed. This examination would provide an estimate of the future population, uses, revenues, and number of school children to help anticipate demands on the sewer and transportation system, traffic, etc. to guide local officials in making planning and zoning decisions.
6. Jim rocked thick-rimmed glasses before hipsters and has the poor vision to prove it
In 2011, in the midst of the financial upheaval at Hoboken's public Hospital, Jim was appointed by Governor Christie to serve on the board of the Hospital's managing organization and helped effectuate the sale and transfer of the Hospital to a private owner, which saved the Hospital, 1,200 local jobs, and freed the City from a potentially devastating $52 million bond guarantee.
7. Jim rocked running shorts before it was hipster and has the marathon medals to prove it
Since 1996, Jim has led the Hoboken Harriers Running Club and its annual charitable events, which benefit local charities such as the Jubilee Center, United Cerebral Palsy of Hudson County.
8. Jim listen to Elvis Costello the first time he was cool
9. Jim created the social causes hipsters are involved with now
As a twenty-five year employee of the U.S. Environmental Protection Agency, Jim is committed to the environment and sustainable solutions to problems. He joined Hoboken's volunteer Green Team to help the City become a more sustainable community, and advocates incorporating green infrastructure into our development decisions. We need incentives for installing green roofs, rain-barrels, rain-gardens, and we need to encourage builders to seek LEED certification, whether in new building or in retrofitting existing buildings, all to help become a more resilient City.
10. Do we have your support for Jim Doyle as City Councilman?
If so, please share this post on Facebook, Twitter, Pinterest…you know the deal. And, Click Here to learn more about the Original Hipster, Jim Doyle.
This post was created by a member of BuzzFeed Community, where anyone can post awesome lists and creations. Learn more or post your buzz!
- Hillary Clinton's campaign was reportedly hacked as part of what appears to be a broad cyber attack on Democrats.
- A federal court struck down North Carolina's voting restrictions, ruling they intentionally made it harder for black people to vote.
- Four people in Florida are likely the first to contract the Zika virus from mosquitos in the US, the state's governor says.


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Larry Brown Sports "Paul Pierce has yet to make an official decision on whether he will play one more season. If he does retire, the Los Angeles Clippers will let him join the Boston Celtics first. In an appearance on "The Vertical Podcast with Woj" this week, Clippers head coach and president of basketball..." July 28
Real GM Basketball "Doc Rivers was asked about trade rumors involving Blake Griffin and his future with the Los Angeles Clippers. "One, I'm glad you asked the question," said Rivers. "It's funny, you don't want to go out and send out a press release every time there's a rumor about Blake. We're hoping Blake ends..." July 28
The Score "Los Angeles Clippers president and coach Doc Rivers says Kevin Durant's camp told him his team was among his top-three choices during free agency this month. The problem: the Clippers were not in Durant's top two. "The first question we asked is 'are we in the top three?' and they said..." July 28
The Oklahoman "According to The Hollywood Reporter, the Rocketeer will soon relaunch. Walt Disney Studios is developing a reboot to be titled "The Rocketeers." The project, in the early development stages, according to THR is being looked at as a sequel-reboot and will be headlined by a black female..." July 28
The Score "Doc Rivers says people need to get any notion that Blake Griffin isn't long for the Los Angeles Clippers out of their heads. Trade rumors regarding the high-flying big man have circulated for months now, but Rivers points out there hasn't actually been any substance to them. "First off, no..." July 28
Bleacher Report "The National Basketball Players Association (NBPA) announced Wednesday it will fund health care for the league's retired players who racked up at least three years of experience, per Howard Beck of Bleacher Report. The statement noted player representatives passed the vote to fund the health..." July 27
CSN Bay Area "On Jan. 23, Blake Griffin sustained a fractured hand after punching Clippers equipment staffer Matias Testi in the face. Testi will not be back with the Clippers next season, according to a report from TMZ. Griffin and Testi got in an argument at a restaurant in Toronto. "It's something I..." July 27
ESPN "Clippers owner Steve Ballmer has begun to explore potential sites for a new Clippers arena, multiple NBA sources said. The Clippers would neither confirm nor deny they are actively searching for a location, but one NBA source said that an area that piques the franchise's interest is Los..." July 27
Larry Brown Sports "Lamar Odom walked out on his family's attempt at an intervention last week, but that is not stopping those close to him from trying to convince the former NBA star to seek professional help. According to a report from Extra, Odom's family is searching for "additional options to present to him"..." July 27
SI "Former All-Star forward Paul Pierce will return to the Clippers next season, reports Brad Turner of the Los Angeles Times. Pierce, who will turn 39 before the start of the regular season, is under contract with Los Angeles for two more years. He signed a three-year, $10 million deal before last..." July 27
Pro Basketball Talk "Clippers president/coach Doc Rivers said he expected all three of his 2016 draft picks to join the team this season. The Clippers signed No. 25 pick Brice Johnson and No. 40 pick Diamond Stone. But No. 39 pick David Michineau will remain in France." July 25
The Score "DeAndre Jordan is a career 42-percent foul shooter, and in Sunday's Team USA exhibition game against China, he missed the only free-throw attempt he got. It was a pretty ugly airball, too. After the game, Jordan's fellow Houston native Jimmy Butler had some sound advice for the big man." July 25
NBA.com "DeAndre Jordan joked that head coach Mike Krzyzewski told him if he didn't do anything in the first 30 seconds Sunday night, he was getting pulled. After getting the loudest pregame cheers and addressing the crowd at STAPLES Center, Jordan kept his home fans amped and made the most of those..." July 25
Yardbarker "It's always hard for the Los Angeles Clippers to evaluate themselves during the summer. Despite consistent success in the regular season, things go south at the snap of a finger when the playoffs roll around. Looking to go up 3-1 in the series, both Chris Paul and Blake Griffin were lost to injury..." July 23
Morning News USA "After missing out on the Pau Gasol sweepstakes in June, the Toronto Raptors are now reportedly setting their sights on another top-caliber power forward. Word around the league is that the Raptors are targeting Los Angeles Clippers big man Blake Griffin. Griffin has a player option in 2017. He..." July 21
Clips Nation "Kevin Durant's decision to flee Oklahoma City to join the Golden State Warriors may have not have had a major effect on how certain teams approached the offseason, but it has cast a sort of pall over the rest of the league. Regardless of what moves other clubs make this summer the Warriors are..." July 20
The Score "The Boston Celtics have plenty of picks and good players, and they may be looking to part with some assets in order to obtain a great player. While they've been linked to stars like Russell Westbrook and Blake Griffin, it's believed the player who's most likely to land in Boston via a..." July 20
Larry Brown Sports "The Oklahoma City Thunder are doing everything they can to avoid slipping into rebuilding mode now that Kevin Durant has left. If they can convince Russell Westbrook to stay beyond the upcoming season, they will try to bring in another superstar to pair with him. The Thunder rescinded their..." July 20
Sporting News "Twitter continues to partner with sports industries, and the latest pairing is with the NBA. The social media company and basketball league made a joint statement Tuesday announcing a deal which allows Twitter to broadcast "exclusive original live programming" from the NBA. But the programming..." July 19
SB Nation "The Washington Post's Tim Bontemps put together a tidy package of flashpoints in upcoming NBA labor negotiations, issues that could be so divisive they could spark another season-damaging lockout. We'll talk more about the Lockout Warning Level as summer wears on, but one item in particular piqued..." July 19
Complex "Sliding into the DMs: everyone does it, even your favorite NBA players. While on the red carpet for this year's ESPYs, SLAM's Alexis Morgan asked a couple of the league's stars whether it really does go down in the DM and they were pretty honest. Following a brief exhale, DeAndre Jordan simply..." July 19
Larry Brown Sports "Blake Griffin has been the subject of trade rumors, but teams may be hesitant to take the plunge due to his recent leg injury. Steve Bulpett of the Boston Herald spoke to an anonymous NBA executive who has fears about Griffin's partially torn quad tendon injury and believes the problem could be..." July 18
CSN New England "With trade rumors involving the Celtics heating up - a three-way deal with the Clippers and Kings that lands Blake Griffin in Boston is the latest - one Western Conference general manager told the Boston Herald that while Danny Ainge is itching to make a trade, Griffin's leg injury could..." July 17
Yahoo! Sports "Despite a strong pursuit from the San Antonio Spurs, free agent Brandon Bass reached agreement on a one-year deal with the Los Angeles Clippers on Saturday, league sources told The Vertical. Bass had been deciding between veteran-minimum offers from the Spurs and Clippers, but the recruitment..." July 17
Seattle Times "Los Angeles Clippers owner Steve Ballmer said Wednesday he doesn't see Seattle landing an NBA franchise "within the next year or two years" to facilitate public funding for an arena. Speaking at the GeekWire Sports Tech Summit at Safeco Field, Ballmer, the former CEO of Microsoft, said there..." July 16
Hoops Rumors "The Clippers will waive shooting guard Devyn Marble, whom they acquired in a trade with the Magic, tweets Brad Turner of The Los Angeles Times. The deal, which was completed earlier today, was viewed as a way for L.A. to reduce salary before signing free agent point guard Raymond..." July 15
Larry Brown Sports "The Boston Celtics continue to be linked to big names, but it sounds like any moves remain far off. Steve Bulpett of the Boston Herald reported Thursday that, while the Celtics have had interest in the Clippers' Blake Griffin and Oklahoma City's Russell Westbrook, nothing is imminent and no..." July 15
CBS Sports "Wilcox (hand) will be traded to the Magic in exchange for Devyn Marble and a 2020 second-round pick, Josh Robbins of the Orlando Sentinel reports. The Magic will also receive a sum of cash in the deal. Since entering the league as the 28th selection in the 2014 draft, Wilcox has been quiet,..." July 15
Clips Nation "According to Dan Woike of the Orange County Register, the Clippers will sign rookie big man Diamond Stone to a contract today Stone was picked 40th in the 2016 NBA Draft last month. Due to the Clippers' cap situation, his contract will be for the rookie minimum: The Clippers have no cap..." July 14
Dime Magazine "When Kevin Durant joined the Warriors, it shifted the balance of power in the NBA to an extent not seen since LeBron James joined up with Dwyane Wade, Chris Bosh, and the Heat in 2011, and raised concerns around the league from everyone to KD's former teammate James Harden to the commish himself,..." July 14
NESN "The NBA offseason is far from over, and the Boston Celtics are right in the thick of things. The Celtics, who lost out to the Golden State Warriors in the Kevin Durant sweepstakes, reportedly have their eyes on some premier trade targets, most notably Oklahoma City Thunder guard Russell..." July 14
Hoops Rumors "The Clippers and unrestricted free agent Raymond Felton have agreed to terms on a contract, Chris Haynes of The Northeast Ohio Media group reports (Twitter link). The length and terms of the arrangement are not yet known. Interest had picked up in the veteran in recent days, as Haynes noted on..." July 14
Sporting News "The Celtics are up to something. Talk to any front-office executive here at the annual Summer League festivities, and the consensus is that a major deal involving Boston is coming soon. But it might not be the deal most were expecting. While speculation has held that the Celtics would pursue..." July 14
TMZ "Lamar Odom made it to NYC after all and looked fully recovered from his puking session on the plane ... because he beelined it for a strip club. Lamar was photographed hanging with friends and staffers at CityScapes Gentlemen's Club in Queens on Tuesday night. A far cry from his Monday night --..." July 13
Obsev "The Boston Celtics have been quiet since acquiring Al Horford and failing to recruit Kevin Durant. But that doesn't mean GM Danny Ainge hasn't been making phone calls around the league. The man who famously brought Kevin Garnett and Ray Allen to Boston in 2007 is looking to make another..." July 13
Bleacher Report "The NBA announced changes to its intentional fouling rules Tuesday following years of debate regarding teams' various Hack-a-Shaq strategies. According to the league's official press release, the NBA Board of Governors approved a rule change for the 2016-17 season that will make the intentional..." July 13
Hoops Rumors "The Clippers have locked up their 2016 first-round pick, according to Dan Woike of The Orange County Register, who tweets that the team has signed Brice Johnson to his rookie contract. The team held a presser earlier today to introduce Johnson along with second-rounders David Michineau and Diamond..." July 12
Larry Brown Sports "Lamar Odom was reportedly removed from a flight on Monday night because he was drunk and vomiting. Witnesses told TMZ that Odom spent a good amount of time in the Delta lounge at LAX airport prior to boarding his flight for NYC and was "pounding down beers and whiskey." He was described as..." July 12
Larry Brown Sports "Lamar Odom is looking for a new roommate or a place to live. Since he was released from the hospital after nearly losing his life to a drug overdose, Odom had been living in a rental home that his estranged wife Khloe Kardashian rented for him. The home was in the same upscale Calabasas..." July 11
Real GM Basketball "While Paul Pierce has yet to make it official, a person close to him says he intends to play next season. Pierce has been considering retirement and had a successful run with ESPN during the playoffs. " July 09
Hollywood Life "And that's a wrap, folks. Khloe Kardashian and Lamar Odom have now BOTH agreed to end their marriage, as the former NBA star finally filed his own divorce documents, TMZ claims. To find out when they split will be official, keep reading. Lamar Odom has finally filed his response to Khloe..." July 09
Yahoo! Sports "Free agent Marreese Speights has reached agreement on a deal with the Los Angeles Clippers, league sources told The Vertical. The Golden State Warriors lost the flexibility to retain Speights after the arrival of free agent Kevin Durant and the signing of David West, clearing the way for..." July 08
ESPN "In a surprise turn, the NBA is pulling back on its salary-cap projection for the 2017-18 season, according to a league memo obtained by ESPN, and it could complicate the Golden State Warriors' efforts to keep their new super team together. The league previously projected the 2017-18 cap to hit..." July 07
Pro Basketball Talk "C.J. Wilcox has played just 268 NBA minutes across two NBA seasons — not because Doc Rivers doesn't like him, but a combination of injuries (shoulder right after his draft) and the Clippers having some guards that soak up a lot of minutes just didn't let him get on the court. This isn't going..." July 06
Covers.com "Well, this is certainly a holiday weekend that Bay Area basketball fans will never forget. We were told to expect an announcement in the Kevin Durant free agency sweepstakes at some point over the weekend, and the bombshell dropped just before noon EST on July 4. Former Oklahoma City Thunder..." July 05
Los Angeles Times "If at first you don't succeed, make a better offer. The Clippers retained the heart of their second unit on Sunday after vastly improving their proposal to Jamal Crawford. The star sixth man agreed to a three-year, $42-million contract after an initial smaller offer had left him hesitant..." July 04
Clips Nation "According to Adrian Wojnarowski of The Vertical, Clippers incumbent starting small forward Luc Mbah a Moute will return to the team. This deal is likely for the Clippers' bi-annual exception of $2.2 million. I'd suspect there is also a player option for a second year and 2.3 million. The..." July 04
Yahoo! Sports "Free-agent guard Jamal Crawford has agreed to a three-year, $42 million deal to return to the Los Angeles Clippers, league sources told The Vertical. Crawford had discussed one-year deals with several teams around the league, but focused on his negotiations with the Clippers, sources said. The..." July 03
Sactown Royalty "With roughly $20 million of open cap room remaining after signing Arron Afflalo and Anthony Tolliver, and before accounting for Rajon Rondo's cap hold and whatever comes of Seth Curry's free agency, the Kings have been linked to a few more solid veterans over the last 24 hours. The first two..." July 03
Liberty Ballers "Despite the signings of Jerryd Bayless, Ben Simmons, and Timothe Luwawu-Cabarrot, the Philadelphia 76ers still have upwards of $50 million in space as they look to even sniff the salary cap floor. One target the Sixers are reportedly throwing big money at: Los Angeles Clippers guard Jamal..." July 03


text:
Intermediate French Horn Solos, Vol. I (Dale Clevenger)
To play the media you will need to update yourFlash plugin.
French horn
Instrumental Solo Part and CD. Published by Music Minus One (MO.MMOCD3513).
Item Number: MO.MMOCD3513
ISBN 1596152125. Soloist: Dale Clevenger, French horn; Accompaniment: Meg Bachman Vas, piano.
The beginning hornist who has graduated to the next level will find a treasure-trove of gently advancing technical tricks with virtuoso Dale Clevenger of the Cleveland Symphony. Listen as he plays each of these solos. Then take his place as you graduate to the ever more challenging world of an exciting and broadening repertoire!
Includes a high-quality printed solo part containing the solo part, annotated with performance suggestions; and a compact disc with complete versions (with soloist) followed by piano accompaniments to each piece, minus the soloist.


text:
Star Wars Episode III - Revenge of the Sith Rewrite
View Single Post
@Black Knight of Keno
Words. Words everywhere.
Join Date
: Oct 2003
: Bergen, Norway
: 3,942
Mace Windu stood inside a LAAT/i, holding onto the net above him to keep his balance as the gunship rushed towards the Jedi Temple. The droids had been driven back even if he had been too slow to notice the true intention of the attack, causing Grievous to manage an escape with the Supreme Chancellor. But it was not a complete loss as Grievous had been wounded in the very short-lived duel of Windu and the cyborg. The gunship continued to shoot into the diminishing ranks of the droid forces while on it's way to bring Mace to coordinate the swift counter-attack. The gunship had barely landed inside the hangar when Windu jumped off and rushed towards the war room. Inside, he met up with several clones and Jedi giving out orders.
"General Windu, the droids are in a full retreat. Our ships are cutting throught their lines like a vibroblade throught butter" a Clone said as soon as the Jedi entered
"Good. How is the space battle going?" Master Windu asked and walked towards the Clone.
"The Seperatists are attempting to fall back but we have manage to lock them inside the planetary shields. Home Fleet and the Open Circle fleets are continuing the attack and we have recieved word that General Kenobi and Commander Skywalker are on their way towards the
Invisible Hand
" the clone answered and Mace nodded silently, stepping forth to the large table showing the battle rather accurately. depending on which reports were coming in at the moment. Radio communications were tuned over to Kenobi and Skywalker's frequency and their chatter came throught the speaker. Windu nodded to the Clone and started to hand out orders to the Home Fleet on how to position itself
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text:
Bushell's Best Bits of 2012
During 2012, Mike Bushell has continued on his mission to encourage more people off the sofa at the weekend and into sport.
Every Saturday he profiles and personally tries a new sporting activity or new initiative: showing what it's like at the top, and how accessible it is to mere mortals.
Since he started in 2006, he has featured over 300 alternative sports and is still going strong, with new ideas coming in all the time. Please suggest any you may have.
Here's a look back at Bushell's best bits of 2012, which involved taking tips from sporting superstars like Louis Smith, Wladimir Klitschko and Shane Williams.


text:
Boston.com -- Latest news, Boston Globe
Mon, 07/16/2012 - 10:49am
Wopular is an
online newspaper rack,
giving you a summary view of the top headlines from the top news sites.
Senh Duong (Founder)Wopular,
Broadly viewed, Terry Ryan's dismissal as Twins GM a week ago came as a result of bad decisions in talent evaluation. You don't fire someone at the top of the personnel food chain, after all, if a roster is stocked with complementary, talented pieces.
Narrowing the view, pitching was the critical area with the most missteps, both in terms of organizational development and outside acquisitions.
I'd posit there is another narrow view of what went wrong — much of it, still, in the pitching department but also spread across the roster.
It is this: the Twins under Ryan fell victim too many times to small sample size decision-making, particularly when the small sample was positive.
Four Wisconsin organizations that integrate a social or environmental mission into their business will be awarded $25,000 each through a new state competition, WARF said Monday.
The mayor of Baltimore officially launched the convention instead.
Some are angry that Sanders endorsed Clinton.
Here's a list of the first days of school at Des Moines metro area schools. (You're welcome, parents.)
Harold Vietor, a highly respected state and federal judge in Iowa who served on the bench for five decades, has died.


text:
|No such thing as a small change
Re^2: Programming patterns (cohesion)by chromatic (Archbishop)
|on Jun 22, 2012 at 18:34 UTC ( #977882=note: print w/ replies, xml )
|Need Help??
I also found it amusing that chromatic's best example in explaining "Replace Conditional with Polymorphism" was that:
Neither the post nor that example is about "Replace Conditional with Polymorphism". As you imply, that pattern is a specific case of the more general "Reduce Conditionals".
In Section Meditations


text:
Skip to Main Content
IEEE membership options for an individual and IEEE Xplore subscriptions for an organization offer the most affordable access to essential journal articles, conference papers, standards,
eBooks, and eLearning courses.
Learn more about:
IEEE membership
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The dependence of Tb and Co concentration on the magnetoresistance (MR) of TbFeCo amorphous films with perpendicular magnetic anisotropy have been studied at room temperature. TbxFe(88-x-y)Coy films (where x=15--37 at% and y=5--25 at%) with thickness of 200 nm are deposited by dc-magnetron sputtering. The MR ratio is sensitively dependent on the Tb concentration. The MR ratio is increased up to about 2.8% for a Tb concentration of about 22.4 at% then decreased for more Tb content. No significant effect of Co concentration on the MR ratio has been observed. The relation between MR ratio and film composition can be ascribed to the dependence of the domain wall width on the film concentration. The domain wall width decreases with an increase in Tb concentration and again increases for more Tb content showing its minimum value at about 22.4 at % of Tb concentration. It may be considered that the observed MR is contributed from the domain wall.
A not-for-profit organization, IEEE is the world's largest technical professional organization dedicated to advancing technology for the benefit of humanity.© Copyright 2016 IEEE - All rights reserved. Use of this web site signifies your agreement to the terms and conditions.


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14 条留言
Definitely one of my fav record labels atm, they seem to have some serious taste in quality music and the bands that they sign and expose!
My band From Existence is working on our debut EP that will be released soon, early 2014, would fit beautifully in your roster.. if ya know what I mean XD
<3 çok ıyısınız amk
Please join in the Evita group. <3
ordered your hoodie!
keep this shit pumpin. much love
<3 From the Djentlemens Club www.facebook.com/djentlemen
Hi guys. Much love.
Dom from Soundspheremag.com.
pure progressive math and technical metal bands great label
Some top bands on this label! Please check out some fine UK industrial metal at: http://www.last.fm/music/Violation+Complex/Violation+Complex+-+Demo+2009 - Thanks :o)
Right guys, we have decided to give our EP away for free, simply clicking either of the links below. All we can ask from you is to send it on to anybody that you think will enjoy it, even to those who you think wouldn't like it!!! If you want to check us out go to www.myspace.com/thesafetyfire Please help spread the word!! If you feel so kind grab some of our merch as well Click link for free EP http://dl.getdropbox.com/u/765705/TheSafetyFire.zip
What about Gehenna VII VII VII, they are fucking A!
some great bands in the making here!


text:
OSI-Approved Open Source (4)
- GNU General Public License version 2.0 (2)
- PHP License (2)
- Academic Free License (1)
- Apache Software License (1)
- Apple Public Source License (1)
- Common Development and Distribution License (1)
- Common Public License 1.0 (1)
- Computer Associates Trusted Open Source License 1.1 (1)
- Educational Community License, Version 2.0 (1)
- Python License (1)
- Python Software Foundation License (1)
- W3C License (1)
- Public Domain (1)
Development Software
BADEL- Binary Automated Data Exchange
Binary Automated Data Exchange Language (BADEL) ornate systems; kernels for BADEL chests, resorts/settlement codes, argument prompts, nests for FIN/POD, datelines, operating data and nomenclature claims. Requires SuperWikia Alpha Mainframe frameworks.
Divine Logic
The future of information technology will be based on controlling the flow of natural light. This project is an attempt to establish the code (or software) that will enable this to happen. It involves rewriting an OS from the ground up.
Muhha! The open source GPU compiler.
Muhha is a GPU compiler/interpreter for Mac, Windows and Unix. Compiles 3D graphics for OpenGL and DirectX9 and is compatible with Blender, ORGE, PoserPython, Collada and Dark Basic programming. Powered by KomodoEdit and .NET.
Tweepcraft-OS- Runtime figures animation
Tweepcraft-OS is a 3D human model and prop simulator for SuperWikia Alpha. Using Tweepcraft-OS 3D prescriptions and extensions, users may improve animation, voice over lip syncing and other runtime features. Requires SuperWikia Alpha, Wobba Wobba and


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Choose your preferred language. We speak English (US) and 41 other languages.
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Very good
2,767 reviews
Within 2 blocks of Lake Michigan and the Museum of Contemporary Art, this downtown Chicago hotel features free Wi-Fi. Its apartment-style accommodations have a full kitchen.
"Excellent location, spacious room with fully equip…needs additional info, because I was without car."
600 reviews
This charming historic hotel is situated within the Lincoln Park and Lakeview neighbourhoods of Chicago. It offers European-style guest rooms and serves a daily continental breakfast.
"I love the parking, the staff was great and the 2 bathrooms in our room was terrific!"
1,063 reviews
In the heart of downtown Chicago, seconds from the Magnificent Mile area and popular attractions, this hotel features exceptional accommodations complete with an on-site restaurant.
"Location is excellent! Room is quite spacious! Nice in general!"
392 reviews
In the heart of the city, steps from major attractions, including the luxury shopping of the Magnificent Mile, this hotel offers modern fitness facilities, on-site dining and modern accommodations.
"location, breakfast, facilities, staff very helpful."
497 reviews
This all-suite hotel is in downtown Chicago, surrounded by upscale dining and shopping in the trendy River North neighborhood. It features a breakfast buffet and free Wi-Fi throughout the property.
"The staff was very helpful and nice to us! The b…m was clean and confortable. Very good location."
Very good
945 reviews
Boasting an outdoor pool in the heart of downtown Chicago, this hotel is located within 5 minutes' walk of the famous Magnificent Mile. It has 2 on-site restaurants and a flat-screen TV in every room....
"very clean very comfortable helpful staff, friendly"
416 reviews
Located in the River North district, this downtown Chicago hotel is 1 mile from Navy Pier. The all-suite hotel features an Italian restaurant, indoor pool and suites with 2 flat-screen TVs.
"Downtown, close to L train, very safe, good locati…, extra charge, but that's standard downtown."
391 reviews
In Chicago's cultural district, this hotel is in the same historic building as the Bank of America Theater. It serves a hot breakfast buffet every morning.
"Localization exelent, near important places as Milenium Park, etc"
Very good
682 reviews
This downtown Chicago Hotel is just a 5-minute drive from Wrigley Field. It features an on-site fitness center. All guest rooms include free Wi-Fi.
"Ticked all the right boxes for us"
1,038 reviews
Across from Grant Park and within walking distance of several popular Chicago attractions, this hotel features an on-site restaurant, seasonal outdoor pool and comfortable guest rooms with free WiFi.
"A short walk to everything downtown. Great service, very friendly and informative."
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Skip To Navigation
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Alberta.ca > Justice > Browse by topic > Public fatality inquiries > Office of the Chief Medical Examiner > Settling of estates
The Office of the Chief Medical Examiner (OCME) has the authority to complete proof of death documents when it investigates a death.
In this situation, neither the hospital or the deceased's family doctor has the authority to complete these documents. A medical examiner from the OCME must complete all documents about the cause and manner of a death.
The OCME only releases certificates, reports and forms for a specific death after a medical examiner completes their investigation of that death.
Institutions such as banks, insurance companies and legal firms usually require an official proof of death document before the deceased's claims and other dispositions may be settled.
This gives the deceased's name, sex and age, plus these details about their death:
To order
Fill in the Request to Access Information form.
To authorize a third party to request information, fill in the Consent to Disclose Information form.
The Alberta government's official certificate of death is:
The certificate gives the deceased's:
To obtain a death certificate, contact your local registry agent.
A medical examiner performs either an autopsy or external examination of the deceased.
If a medical examiner performs an autopsy, the OCME prepares these documents:
Note: The OCME prepares an Autopsy Report or External Examination Form, but not both.
If a medical examiner decides that an autopsy isn't necessary, they perform an external examination of the deceased. Afterwards, the OCME prepares these documents:
Note: The OCME prepares an External Examination Form or Autopsy Report, but not both.
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Now that school is out for summer, does anyone have any summer vacation plans?
Summer holds nothing different for us, sadly. No vacation this year since I depleted all my time for maternity leave. boo!
We have 3 camping trips planned, 2 long weekends and 1 full week. Very much looking forward to them. Other then that it will be about trying to stay sane with all 3 kids home. I will be very much looking forward to September when Coleson goes to school full time and Sarah will be in nursery school part time.
I don't really have any plans. DH gets to take leave starting Friday so I'm pretty excited about that. We've discussed maybe going to the beach, but I dunno. It'd be a 3-4 hour drive and I'm not sure I want to drive that far yet with Desmond.
Saturday we're doing pictures and the next weekend is our garage sale and then his leave will be up so...lol. We definitely need to get the kids out more
We're too poor. It'll likely be years before we get any kind of vacation.
We don't have anything "exciting," per se... but today is my 30th birthday, July 8 is DHs 30th birthday, and July 11 he is having shoulder surgery. Then, the kids have soccer camp the third week of July and vacation bible school the following week. I just completed my associates degree a few weeks ago, and I'm continuing with part-time classes toward my bachelors degree. Some time in August, we are also trying to plan a camping trip with my dad and step mom. So... a lot of busy, but nothing super fun..
Happy Birthday!!
My girls, husband and I are heading to Toronto for the Assembly of First Nations elections in July.. that is the biggest excitement for the summer... after that we are going to be living on a tight budget since he just found out yesterday that he is laid off as of the day we fly... crappy.. but he is already looking at other job postings, so fingers crossed.. Otherwise, it is me and the four kids hitting the parks, beach, etc for the summer!!


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just got started with XNA and this example would help out a lot!
I´ve done a simple test where i got some terrain and a ball, when the ball hits the terrain it stops. This i do by setting the ball position to just on top of the terrain on collision.
To my question, im using bounding box for this, but it doesnt look very well if the ball hits the terrain from the left or right side since it respawns on top. How do i check of it hits on side?
Short glitch of the code right now:
if (playerOne.BoundingBox.Intersects(terrain.BoundingBox)
playerOne.Position.Y = terrain.BoundingBox.Top;
Where playerOne is the ball.
Thanks in advance!


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you are viewing a single comment's thread.
Wishful thinking in this crappy market but I would love see $180 to $200 tomorrow.
I still feel that if e/r is good, could possibly run mid 140's to maybe 150. Profit taking soon after. I just do not see 180-200. Would love to but don't see it.Good luck.MG


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January-March 2012 FPMT HISTORY Big Love , the long-awaited authorized biography of Lama Yeshe written by Adele Hulse, provides an intimate portrait of FPMT's founder. This excerpt is taken from the chapter chronicling the 1982 Enlightened Experience Celebration Bodhgaya: The …
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text:
Satisfied with the springs I received
Reviewed By Juan C (OXNARD, CA) Reviewed for a 2015 Chevy Camaro —7/20/2016 11:05 AM
I wanna thank auto anything I'm very satisfied with the eibach pro lowering kit that I got an it only took couple of business day was glad they arrived early they made a big change on my 2015 camaro Ss Jst berly getting it ready for the track thanks again auto anything I recomment them anyone who's trying to lower ur car !??
Eibach zo6 front roll bar
Reviewed By Nathaniel R (TRIANGLE, VA) Reviewed for a 2009 Chevy Corvette —7/13/2016 7:54 AM
Eibach should have ALL their products painted the Eibach famous red color. These were black like the stock ones. May have noticed a little itty bitty difference, but once someone drives the car other than me, they will say the car rides pretty darn good.


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Source: Samsung
quote: It has a screen that gives substantially lower battery life
quote: I don't remember for sure, but bad choice if you did.
quote: no one can say it isn't different
quote: Thankfully, Samsung hasn't stooped to branding it a "Selfie" camera like its competitors. - See more at: http://www.dailytech.com/Article.aspx?newsid=36498...
quote: Quite frankly, we don't see the point and it looks rather odd since it curves on only one side of the device.