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Way to go dvmcc; never let the facts get in the way of a mis-directed public lynching. I would like to see this issue brought forward for full disclosure, and discussion. But by now we should all know better than to follow Tim off a cliff. Seems to be some serious contradiction between Tim's reporting/presentation of the facts, and the real facts. What's the scoop, scoop?
One thing I will give progressives kudos for, is their success in indoctrinating the past couple of generations with the belief that if the government doesn't "take" something from you or from your business, the definition of that action is really "giving" you something. This very basic misunderstanding results in confusion for those with limited powers of critical thinking, which results in news articles that perpetuates the myth, which results in further confusion.
During these very difficult times let us all try to get our heads around a simple fact.
-If the government; local, state or federal, was taxing a person or business at say 35 percent of their income (profit), and for whatever reason the government opts to only extort 30 percent, a fair description of this action would be that the government is letting the person or business keep their own hard earned money. Only someone with an ulterior motive would define this as "giving" them something. To give something would mean that you had right of ownership in the first place. Regrettably, there is now a percentage of our country that believe it is their right to be re-distributors. In their reality, all the assets are communally own, and if by ingenuity and hard work someone should end up with more than someone else, it's only FAIR that we extort a large percentage of one persons earnings and re-distribute that to others, that likely made bad choices and didn't work nearly as hard. If by some strange reason we collectively decide maybe we'll let the earner keep a larger share of what he earns; then it's only FAIR that we define this action as giving them something.
In other times and other places this philosophy would be called socialism or communism, where the community owns everything, and for your hard work they get to decide what you get in return. If that is not destructive enough of the human spirit, when the state does doles you out your portion, they remind you that they are "giving" you something. News flash. This doesn't work, just ask Russia, all of eastern Europe and Cuba, where they had/have to trap people inside to prevent them from escaping. America is great for one primary reason; Freedom. The more we allow the government to believe what is our, is theirs, the less freedom we will have to make our own choices. As we are seeing now, less freedom results in less prosperity. They go hand in hand.
What I find curious is that virtually all media commentary extols the virtue of moving to the center, yet our current President lives on the left fringe, with the Rev. Wright and Saul Alinsky. If the majority of Americans do indeed view themselves as conservatives, why is the best strategy for the GOP to automatically shift to the mussy middle. Will we find the Obama campaign moving to the middle, or will the strategy continue to be to pit one American against another, and to vilify success, while pandering to those that expect a hand out. I don't believe any of this attempts to find the middle.
What is Current TV?
The education system in this country (especially at the university level, where there are zero checks and balances) is just one more example of how to much federal government involvement, results in a run away train wreck. There are too many examples to list here that prove this to be true, but if you were to get a list of all of the employees at U of M that made over $50,000.00/year, the job titles would cause your eyes to roll back in your head. I don't take issue with the top earners listed in an earlier post, although they seem excessive to me. Where the real scandal can be found is in the number and level of pay that can be identified as going to non-teaching staff. Over the past couple of decades there has be an explosion of administrative positions added on college campuses for non-teaching staff with job titles that are 4-6 words long. At some colleges the payroll for non-teaching staff, exceeds the payroll for the actual educators. All of this excess is paid for through federal and state funding and grants. Then, what isn't paid for directly by the government, is covered in large part by government subsidized, and government backed student loans. If this isn't enough government intervention, our enabler-in-chief Barak Obama has recently announces that by executive order his administration was going to put in place a program that allowed for large portions, and in some cases all, of future student loans underwritten by the federal government to be forgiven, if the people who originate the loans were unable to pay them back after 20 years. This program I'm confident will become, a major component of the President's future stump speeches on college campus. Both the college employees and the students will love to hear this. From the students perspective they'll be even more casual about incurring un-reimbursable debt, knowing that it eventually will be forgiven with out penalty. While campus employees will be happy to hear the the gravy train will keep on rolling, paid for by even higher tuitions, supported by even more government funding, masquerading as student loans. (only in America)
Dordt College students = Spoiled rich kids whose parents work hard so they can go to expense colleges, who have been indoctrinated with the liberal screed that social justice can only happen through a federal government (that is 15 trillion dollars in debt). This weak thinking is the progressives means of justifying their own individual lack of effort and commitment to make an individual effort make a difference. Lazy liberals have been conditioned to be politically correct in their words (which includes demagoguery of free market principles), and show up at a protest or two, and call it good. Going to bed at night believing they've done their part to help their fellow man. Meanwhile, the economy crumbles due to a corrupt, inept monstrosity of a federal government that seizes more and more control of our lives, and the number of unemployed grows and the poor get poorer. Shifting our personal responsibilities for ourselves and our fellow man, out of laziness, and weak mindedness will result in the end of a free society, that was not so long ago a beacon of light, to the truly oppressed of the world.
I appreciate Britta's insight, and agree good answers are difficult to come by. However, aside from the heinous behavior of the predator, and the inexplicable inability of any number of people who could have put a stop to his actions, there seems to be an over emphasis to acheive some type of retribution, and to tear down an institution, and a program that aside from a few misguide people, didn't do anything wrong. Should the running back for the Penn State who work hard for the past decade, to achieve a personal goal for himself, be punished and his future altered because of the actions and inactions of a few men 8 years ago? Is that really appropriate. To David Brooks point; if the predator ran the English department 12 years ago and this horrible litany was put out on display this week, would the righteous and pious be calling to shut down all academic classes. I think not. Further, I wonder, would we even know about it. I believe that every effort should be made to complete a full investigation, and criminally punish all those that have broken our laws. I even believe removing Joe Paterno is likely the correct action in attempting to move forward, but any call to punish the students, and cancel the rest of the season is misguided misplaced ineffective retribution.
Mr. Branson,
I appreciate your effort. However, I can't resist the urge to respond. Your civility and concern are welcome. But it is obvious to this reader you can not even recognize your own partisanship. You deride every attempt by the Republican's to explain their resistance to the any plan that includes raising taxes on the job creators, spending additional money we don't have, and giving tax breaks or government gifts to select groups, and then try to dress it up like a jobs plan. As a society we have evolved into 2 disparate groups. The vast majority of us want the same goals and outcomes. Through our experiences as collective groups we have over time, just hardened our beliefs on how this is to be accomplished. The side you have obviously chosen, believes the government has the ability to create jobs. The side I've chosen believes the only jobs government has the ability to create are government jobs, which only create more regulations, that take away personal freedom, and responsibility, and don't actually produce a single positive thing. From my perspective the President promised to bring us together, and to work with Congress, to take steps to improve the lives of all Americans. After almost 3 years the atmosphere is more divisive than ever, and the President and Congress have not worked on anything together to attempt to improve our dismal condition. Please spare us the rhetoric that this is due to the Republican's being the party of "no". ObamaCare was jammed down the countries throat, despite the objections of the people, much less the Republican Party. People can say want they want about President Bush, at least he tried to reach across the aisle, to make progress through compromise, through the No Child Left Behind bill that was written by Ted Kennedy, and the Prescription Drug bill for seniors written by Sen Tom Daschle. Certainly, neither is these programs, which expand the size and expenditures of the government, could have been considered high on the conservatives wish list. Yet no sooner had the paint dried on both of these bills, both Senators Kennedy and Daschle wasted no time in turning on the President, attacking him as a person, and undermining his efforts as we were under attack by outside forces. Finally, you conveniently have left out the fact, that despite the Democrats control of the Senate, they have resisted bring the President's Jobs bill to a vote, because Mr Reid knows that despite his majority, they don't have enough democrat votes. So it is not just the Republicans that are holding up the bill the President has so eloquently demanded be past "right now", more than one month ago. Today, as is the President's typical pattern, Mr. Obama is on the campaign trail, misleading the American public, by assuring them that if this most recent effort of a re-distribution bill isn't past, we will enter into a recession. Pure demagoguery.
STOGamer; never said it was the governments problem. Didn't even say it should not have happened. You should learn to read the words instead of jumping to your own conclusions. The point was; that there are agreements and understandings made all the time in free enterprise and in government. Speaking of social programs I noticed you chose not to touch the government Ponzi scheme that we call Social Security. In the case that is addressed in the article there was no contract. only an ill conceived government program, that is now being eliminated, because it is unfair. As for waking up; in your fantasy world, just who do you think is getting rich on any of the current Governor attempts to fix the mess the previous Governor has left him?
STOGamer; never said it was the governments problem. Didn't even say it should not have happened. You should learn to read the words instead of jumping to your own conclusions. The point was; that there are agreements and understandings made all the time in free enterprise and in government. Speaking of social programs I noticed you chose not to touch the government Ponzi scheme that we call Social Security. In the case that is addressed in the article there was no contract. only an ill conceived government program, that is now being eliminated, because it is unfair. As for waking up; in your fantasy world, just who do you think is getting rich on any of the current Governor attempts to fix the mess the previous Governor has left him?
Good response "card20a";
Paula what contract? Is it signed by the governor? The answer is no. It's a promise. Well, after decades a political gerrymandering, there are more promises than we can sustain. Is the 100's of 1000's I paid into Social Security, but probably won't see a penny of, a contract. How about our family health insurance that was a part of my wife employment but was withdrawn effective 10/1/11, wasn't that a "contract". Time for Americans to wake up. The government has been mucking up the free enterprise system for decades, picking winners and losers. Now that they have broken the system, it's time we get back to basics, and let people and private enterprise stand on their own two feet. No more tax breaks, incentives, or credits, based on arbitrary elitist objective. You pay yours and I pay mine.
We'll see who's popular and who is not 11/4/12.


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Burton Albion boss Gary Rowett wants to build momentum over next two games
Posted: February 24, 2014|
GARY Rowett is hoping to get back to winning ways at Torquay tomorrow night after Friday's disappointment at Bristol Rovers.
The Brewers went down 2-0 at the Memorial Stadium after a flat performance against the Gas.
Now, Albion travel once more to south west – and Rowett wants three points ahead of Saturday's home clash with Accrington.
"Certainly we'll be going down to Torquay to see if we can get something out of the game there and then use that as a springboard to go and win our home game against Accrington," he said.
"That's it – it's about winning games.
"We gave the players Saturday and Sunday off – they needed a breather to recharge their batteries and get ready to kick on.
"We've still got lots of games coming up and I think at the moment the conditions make the games heavy and hard.
"Training is quite heavy and hard and it takes a lot out of your legs.
"These journeys don't help but we've got to make sure that we navigate them."
Rowett is keeping Friday's defeat – a first on the road in 2014 – in perspective.
Albion are still well in the promotion race sat in sixth spot and are only five points off the automatic promotion places.
Saturday's results could have gone much worse, with Fleetwood and Chesterfield both losing and Southend and Oxford both getting draws.
"We'll have a look at the table after the weekend and we'll be in exactly the same position, whatever happens," said Rowett.
"It's a bit cliched, but if you'd told me after last season after 32 games or whatever it is, we'd be in this position I'd have been quite happy.
"Look at how Northampton have coped and look at how Cheltenham have coped (the season after reaching the play-offs.
"We've got a lot to shout about.
"Sometimes you raise expectations and everyone is almost disappointed when you come to Bristol and lose.
"What I would say is that's the best we've done at Bristol over the last three games! (after 7-1 and 3-0 defeats).
"I'll be really, really looking forward to the next trip here - it's my favourite place in the world at the moment!"
For tomorrow night, Damien McCrory should be back in contention after missing Friday's defeat with a dead leg.
Michael Symes (knee) will not be pushed too soon.
"We've only got Symesy out and Damo I think possibly will be available," said Rowett.
"I don't see any reason why Damo won't be okay.
"It'll only be Symesy out and I don't think he'll be quite ready to come in, just because he hasn't trained enough.
"I don't think bodies are our issue. We let Zander go out in the week and we're okay in those positions.
"So, really it's a case of can we score more goals and create more chances?"

subset: commoncrawl


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In the last week I've been asked at least 27 times what I'll be dressing up as for Halloween. It's hardly surprising; last year's outing as Bondage Maleficent certainly dropped a few jaws, so it'll have to be something pretty spectacular to follow that. > DISCOVER MORE
Sleek, streamlined, fast and flashy, the Art Deco movement was a seriously sexy design fad. One minute the world was still pining for the fin de siècle and William Morris's flowery tapestries, the next they were up to hi jinx in fleshy pink apartment buildings in Miami. Jiving, driving, and getting up to no good – what more could you want from an era?
Image taken from AnOther magazine > DISCOVER MORE
A hyper feminine sexiness is unleashed for the Agent Provocateur Autumn Winter 2013 collection. > DISCOVER MORE


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(June 2006 Kathryn Brown)
Prior to starting the extractions, add 500µl Buffer RLT to 2mL screw top tubes half full of beads (they can soak overnight). Vortex and centrifuge to remove trapped air. Wipe surfaces down with RNase Away.
For cells collected on filters and frozen at –80° C use:
- determine the number of samples or extractions.
- Wash samples with Buffer RLT. For each sample, 1.2mL of Buffer RLT is needed with fresh addition of B-mercaptoethanol (stable for one month, 10µl B-mercaptoethanol per 1mL of buffer RLT). Tip: Keep tubes on ice. Keep pipette tip used to wash filter paper for transferring to 2mL screw top tubes
- Obtain pre-soaked beads in screw top tubes; add 1.2mL of sample to tubes. Bead beat 2 minutes with Mini-bead beater
- Centrifuge 3-4 minutes at max speed. Transfer 'supe' (discard pellet, the insoluble material) to the old labeled 15 mL conical tube (cleaned with a little 70% EtOH, ~0.4mL).
- Add an equal volume of 70% EtOH (made with 100% EtOH and DEPC water) to the cleared lysate and mix well by pipetting. Tip: Keep the same pipette tip used to transfer supe in the 15mL conical tube for applying the sample to the RNeasy mini spin columns
- Apply 700µl of sample at a time to labeled RNeasy mini spin column (in a 2ml collection tube). Centrifuge each time for 15 seconds.
- Repeat until the entire sample has passed through the column.
- Pipette 700µl of buffer RW1 onto the column, centrifuge 15 seconds.
- Discard flow through and collection tube
- Transfer RNeasy column to new collection tube. Pipette 500µl of Buffer RPE (ethanol added) onto the column and centrifuge 15 seconds. Discard flow through
- Pipette 500µl of RPE onto column again, and centrifuge for 2 minutes at max speed. Discard flow through and repeat empty.
- Transfer RNeasy column to a new labeled 1.5ml RNase free microcentrifuge tube. Pipette 40µl of RNase free water directly onto the RNeasy membrane. Centrifuge for 1 minute at 10,000 rpm to elute RNA.
- Store at –80oC.
Determine concentration and Purity: Spec and KC Junior
Reference: Brown, K.L., K.I. Twing, and D.L. Robertson. 2007.


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After the enormous success story that is 'TSUNAMI', DVBBS & Borgeous caught the attention of massive anthem creators Dimitri Vegas & Like Mike (famous for chart shredders like 'Mammoth', 'Wakanda' and 'Ocarina'). A collaboration was just bound to happen and now it's here in the form of 'Stampede'! The track builds to incredible heights, playing the crowd with bombastic synth string melodies before dropping into percussion laden sub-kick electro territory. What a record!!!
1. Dimitri Vegas & Like Mike vs. DVBBS & Borgeous - Stampede (Original Mix)


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45063-001: Supporting Development Partnerships in East Asia
Project Data Sheet (PDS): Overview
The TA aims to enhance development partnerships between ADB and PRC and between ADB and MON by proposing a set of policy recommendations that the PRC and MON governments can adopt. Fora at the country level with the highest level of representation will be organized and conducted to identify and discuss issues that can assist (i) the PRC in its transition from middle income to a high income country, and (ii) MON in meeting the development challenges that it faces from boom-bust cycle of ... Read More
|Project Number
|Type or Modality of Assistance
Technical Assistance
|Public sector (Sovereign)
|Approval Numbers
TA No. 7784
|Approval Date
|20 Sep 2011
|ADB Financing ($ thousand)
Public sector management
|Economic affairs management
|Strategic Agendas
Inclusive economic growth (IEG)
Project Data Sheets (PDS) contain summary information on the project or program. Because the PDS is a work in progress, some information may not be included in its initial version but will be added as it becomes available. Information about proposed projects is tentative and indicative.
The Public Communications Policy (PCP) recognizes that transparency and accountability are essential to development effectiveness. It establishes the disclosure requirements for documents and information ADB produces or requires to be produced.
The Accountability Mechanism provides a forum where people adversely affected by ADB-assisted projects can voice and seek solutions to their problems and report alleged noncompliance of ADB's operational policies and procedures.
In preparing any country program or strategy, financing any project, or by making any designation of, or reference to, a particular territory or geographic area in this document, the Asian Development Bank does not intend to make any judgments as to the legal or other status of any territory or area.
View the latest procurement notices for Goods, Works and Related Services, or Consulting Services.


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Memo to Chris Quinn: New York Voters Like Livable Streets
Christine Quinn is not known as a politician who shies away from shying away, but it might be time to ditch her public indifference toward NYC DOT's street safety and public space program.
Monday evening, the Times reported on a Times Square Alliance study that, Great Recession notwithstanding, shows booming growth since 2007. Currently, the district "contributes one-tenth of all of the jobs in the city and $1 of every $9 of economic activity," to the tune of $110 billion per annum — 11 percent of the city's economic output.
Rosemary Scanlon, an economist who has lived in the city since 1969, said the numbers seemed plausible because the area was filled with tourists. Ms. Scanlon, the interim dean of the Schack Institute of Real Estate of New York University two blocks from Times Square, said that earlier studies had shown that people who came to the city for Broadway shows and museums stayed two nights or more, on average, and spent significant sums while in the city.
She said the effects of the transformative power of redevelopment may be most visible west of Times Square, where Larry Silverstein and other developers have built luxury apartment towers in places where no market for them previously existed. (The study gives Times Square credit for spawning all of that construction.)
But the most convincing evidence Ms. Scanlon offered was the newfound respect paid by New Yorkers. "I'm hearing people saying, I know this sounds nuts, but I had some out-of-town visitors and I took them to Times Square," she said. "I find myself saying, I want to walk you down there and I want you to see this."
Though the Times doesn't mention it, "this" refers at least in part to the public plaza installed in Times Square in 2009, a project that transformed the "crossroads of the world" from a gridlocked nightmare to a place people want to be. Judging from the fawning Quinn profile in Elle magazine, however, the back of the "Chrismobile" may not offer the best perspective.


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Free Form Summer Fruit Tart
Servings: 8 people
Preparation Time: 30 min
Cooking time: 30 min
Waiting time: 30 min
Total Time: 1 hour30 min
Category(ies): Tarts
4 cups all purpose flour
1 teaspoon salt
½ cup sugar + 2 teaspoon
¾ pound cold butter cut in ½ inch cubes
1 cup cold water + 2 tablespoons
2 cups of blueberries
3 peaches
6 apricots, pitted and cut in small slices
1 cup of strawberries
1 cup of cherries, pitted and cut in ½
¼ cup of milk for brushing the dough
¼ cup of apricot jam
Easy and delicious, this tart is a version of tarts made decades ago without using a tart pan; a flat tray was usually used.
- In a bowl of an electric mixer fitted with paddle, combine 4 cups flour, salt, 2 teaspoons sugar, and half of the butter. Mix on medium speed for about 3 minutes. Add remaining half butter and 1 cup of ice-cold water; mix briefly for 30 seconds. Remove the dough and flatten into a disc. Wrap in plastic and refrigerate at least one hour.
- Blanch, peel, pit and cut the peaches into small slices.
Toss the fruit with ½ cup of sugar. Roll out dough 4 inches larger than desired and transfer to oven tray. Place the fruits onto the dough and fold edges of dough towards center. Brush dough with milk, and bake for 40 to 50 minutes, until the interior is bubbling and the crust is brown.
- Melt the apricot jam on low heat with 2 tablespoons of water. Whisk to homogenize and boil for a few minutes. Generously brush the top of the tart with the apricot glaze to make it shiny.
- Serve warm with vanilla ice cream.


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Tips for Modding Your Nerf Maverick REV-6
January 1st, 2011I recently acquired a small arsenal of Nerf weapons for the office and being both male and nerd in nature, my first desire was to make them shoot further, faster and better. So I spent some time browsing various Nerf modding sites to see what kinds of things people were doing. There is some pretty creative stuff out there!
I decided for a first project to mod my Mavericks (I have a set of 2). This is the first nerf maverick mod I tried. And what did I learn from this? The whole bit with adding straws and filling in the hole is a total waste of time. After 2 hours of tedious labor, cutting, gluing, etc... the results were mediocre - if not worse in most barrels. In fact one barrel didn't even fire. I read the mod page more carefully and realized the guy who posted this mod had the same problem!
What I realized is if you shave off that lip on the top of the orange caps while removing the air restrictors, you break the factory air seal (which is excellent). You can verify this yourself: Take the stock barrel assembly (before taking it apart), and blow air through the hole while plugging the dart end with your finger. You'll notice there is a pretty good seal there (although the air is being slowed significantly by the restrictor assembly, which you will notice when you take your finger off). I tried the same air test after the straw mod and just as I suspected, air was leaking out from between the damaged restrictor cap and the barrel assembly. This diagram hopefully explains it a bit better:
So in the second Maverick, all I did was remove the air restrictors, but was careful to not damage the outer lip. I just Dremel-tooled the spikes out and left a rough hole in the middle - no need to waste time making it fancy. Air just needs to get through freely.
Adding the straws to narrow the diameter of the chamber (I'm guessing this is supposed to concentrate the output) is a waste of time. Having a good air seal and free flow of air is more important than doing this. The results? My 5 minute mod gun performs much better and didn't take nearly as much fiddling.
The other mod I did, which I think is the most useful of all of them, was remove the tabs keeping the barrel in for reloading so it slides out the full 90 degrees. Makes loading way easier and twisting the gun to close the chamber adds dramatic effect.
I am going to get the Vulcan soon and see what I can do with that too... until then, happy modding.


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The Bachelorette
Ashley Hebert's Sister on What Our New Bachelorette Wants in a Man
We met Ashley Hebert's hot tattooed sister, Chrystie, during Ashley's Bachelor Season 15 hometown date in Maine. 'Memba her? She just spoke to Hollywood Life about what Ashley looks forin a guy.
"She likes guys with Boston accents and tattoos," Chrystie joked, adding, "Ashley is looking for someone who is extremely down to earth and someone who is looking to have a good time. She's not looking for someone who is dramatic, volatile, or [...] has a shady past."
And yet she's looking for him on The Bachelorette. Good luck with that! Don't forget: For every Roberto Martinez there's a Justin "Rated-R" Rego, Kasey Kahl, and Wes Hayden.
Chrystie continued, "The best way to win her heart is to be down to earth and super fun." But don't smoke. And don't expect to get married right away, since Ashley's priority is to finish dental school at the University of Pennsylvania.
Read more from Big Sis at HollywoodLife.com.
Need your daily dose of The Bachelorette? "Like" us on Facebook! After all, you'd get our final rose.
Related Links:
- Ashley Hebert Is Confirmed as the Season 7 Bachelorette
- 4 Reasons Ashley Hebert Will Make a Great Bachelorette — and 4 Reasons She Won't


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Thanks to Philips AVENT for sponsoring this post today.
I'm on the first day of a two-week break from sugar, caffeine, and dairy. This morning I dropped my kids off at school and came straight home. NO COFFEE STOP. I need a medal or some brownie points — or a brownie. Mmm. Brownies.
No. I'm sitting down with my lemon water to share a few links with you. Some things I've pinned or admired over the past couple of weeks:
Philips AVENT Natural Bottles, whose wide mouths make them easy to clean, have new designs: Monkeys and Flowers. If your baby is at daycare, this could be an easy way to make your bottles stand out from the other babies' bottles. New pacifiers are available to match, too.
(These designs are only at BabiesRUs, but clear AVENT Natural Bottles are everywhere, including Walgreens.)
This grey kimono-style top is so sweet and perfect for babies of either gender. $8.99 on zulily today!
Cute idea – make letters out of LEGO for child's room. Via Apartment Therapy.
Wonder twin infant portrait! Wish you had boy/girl twins now? Aren't they the cutest? Photo from Erin Morris Photography, via by Audrey from Mom Generations.
Shadow puppets templates you can print yourself, from Handmade Charlotte. Just add straws.
This post on Alpha Mom is a funny list of tips for maintaining your sanity.
I'm not sure where this came from — I think maybe this etsy store. I'm obsessed with geographically inspired wall art. I'd like to have these showing the three places where my kids grandparents live.
Thanks for spending a few sugar-free moments with me, and to Philips AVENT for sponsoring this post. Did you know their natural bottles feature an advanced anti-colic system, come in glass and polypropylene and the extra soft, flexible nipple shape mimics mom's real breast? Follow them on Facebook if you're a fan!
P.S. The natural bottles go with the breast pump we talked about recently.


text: They're bombing large buildings in densely packed cities. "Hey guys, run..." doesn't give you carte blanche to kill civilians. January 22nd. That's 2 months from now. Tail wags dog. See. Here's your problem. Not everyone who disagrees with you is interested in defending the asshats firing rockets into Tel Aviv and Jerusalem. I don't. I'm stating that Israel's response to provocation over multiple decades now has been to strike back with a combination of disproportionate force and active disinterest in the well being of Palestinian civilians. I won't strain this metaphor any further. The above discussion points are more interesting and less likely to be based on kneejerk emotion.


text:
Terri Hall
Terri Hall, a homeschool mom of nine turned citizen activist, is the founder of Texans for Toll-free Highways and Texans Uniting for Reform and Freedom.
Posts filtered on Tag
Legislature blinks as it contemplates largest tax increase in Texas history
Bill to sell-off Texas highways to foreign corporations dead on arrival in House Yesterday, concerned citizens of Texas challenged the Legislature to stand-up to Governor Perry's road privatization, toll road, and Trans Texas Corridor agenda in a press conference on the South Capitol steps in Austin. Texans demanded the Legislature not just roll over and […] [Read More]
Perry vetoes bill to halt taxpayer-funded lobbying for toll roads
Perry veto ensures citizen lawsuit to stop TxDOT's taxpayer-funded lobbying will continue Friday, Governor Rick Perry vetoed HB 2142 (authored by Rep. Ruth Jones McClendon), which could have settled the issue of the Texas Department of Transportation's (TxDOT) misuse of taxpayer money to attempt to sway public opinion in favor of toll roads, particularly privatized […] [Read More]
Why the fuss about toll roads?
Here's the short list of reasons why toll road policy under Rick Perry has caused a grassroots revolt: higher taxes, greater bureaucracy, and corporatism. When I first learned that TxDOT planned to turn US 281, a freeway already built and paid for, into a tollway, it smelled like a DOUBLE TAX rip-off from the start. […] [Read More]


text:
Feb. 11, 2006
MILFORD, Conn. - The Holy Cross women's tennis team fell to Fairfield University on Saturday afternoon, 7-0. The Crusaders were unable to follow up a victory over the Stags for fourth place in the fall New England Championships.
Fairfield swept all six singles matchups and also won every doubles match en route to the win.
Holy Cross pushed two of the singles matches to three sets on the afternoon. At fourth singles, sophomore Katie Guarino (Reading, Mass.) fell to Alexis Accomando 6-2, 3-6, 10-1. Junior Ginienne Santoro (Guilford, Conn.) won the first set but dropped the match to Cristin Zaccareo 4-6, 7-5, 10-1.
The Crusader women will be back in action on Saturday, February 18 at 6:00 p.m. when they take on Assumption at the Paxton Sports Center in Paxston, Mass.
Final Results
1) Lauren Bonanno (FFD) def. Carrie Simmons (HC) 6-3, 7-5
2) Gabi Davila (FFD) def. Kerry Trimmer (HC) 6-3, 6-2
3) Megan Stauffer )FFD) def. Amy Garrity (HC) 6-3, 6-3
4) Alexis Accomando (FFD) def. Katie Guarino (HC) 6-2, 3-6, 10-1
5) Tiffany Marsocci (FFD) def. Meredith Bacon (HC) 6-0, 6-4
6) Cristin Zaccareo (FFD) def. Ginienne Santoro (HC) 4-6, 7-5, 10-1
1) Bonanno/Davila (FFD) def. Simmons/Trimmer (HC) 8-5
2) Stauffer/Accomando (FFD) def. Garrity/ Melanie Bunke (HC) 8-2
3) Christina Chacharone/Michaela Kehoe (FFD) def. Guarino/Bacon (HC) 8-5


text:
If you play guitar and harp, this the holder you need.
The Lee Oskar Harmonica Holder is specially designed for 10-hole harmonicas. Adjustable, fits securely around the neck. All-metal construction.
Item # 423607 | Condition: Info | Customer Ratings: ( 5 Based on 5 reviews)
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Accidental damage, normalNormal wear and power surges are no longer an issue with these comprehensive and affordable plans. We even pay to ship your gear for repairs. More details.
Covers much more than the original manufacturer's warranty:
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*Limitations and exclusions apply. See terms and conditions for program details
The Lee Oskar Harmonica Holder is specially designed for 10-hole harmonicas. Adjustable, fits securely around the neck. All-metal construction.
Limited warranty against defects in new products.
Now you can get added warranty protection for your new gear. Pro Coverage steps in where the manufacturer's "normal wear and tear" ends. Our PRO COVERAGE program offers you UPGRADED COVERAGE if your product ever fails!
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Excellent Holder, after seeing this style used by other musicians, I did my research and found this one on guitar center's website, of course since this is not a high selling item, (e.g. not that many folks play Dylan or Neil Young), none of the local stores carried the holder, I ordered online and it came in ASAP ground. The reduced width on the harmonica section hold the harmonica much better than a wide holder would.
There's really not too much to say about it. It no doubt does what it's suppose to. The springs are VERY strong. Took some force to get my harmonica in there. This is a good thing if you plan on leaving one harmonica in there. If you have multiple keys, then it might be a little bothersome. You'll have no worries of it falling out though!
The last time I played Heart of Gold with my old holder I looked like I had Osteoporosis- the brace got lower and lower each time I played it. This one does not move, which is what they are all supposed to do, but since we live in an age of manufacturing crap, any company that cares about what they make gets a good rating from me.
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text:
The invention is directed to a device for delivering an active agent formulation for a predetermined administration period. An impermeable reservoir is divided into a water-swellable agent chamber and an active agent formulation chamber. Fluid from the environment is imbibed through a semipermeable plug into the water-swellable agent chamber and the active agent formulation is released through a back-diffusion regulating outlet. Delivery periods of up to 2 years are achieved.
1. An implantable device for delivering an active agent to a fluid environment of use for a predetermined administration period of at least 2 months, said device comprising a reservoir and a back-diffusion regulating outlet in mating relationship, wherein a flow path for the active agent comprises a pathway formed between the mating surfaces of the reservoir and the back-diffusion regulating outlet.
2. The device of
3. The device of
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9. The device of
10. An implantable active agent delivery system for delivering an active agent to a fluid environment of use for a predetermined administration period of at least 2 months, said agent being susceptible to degradation if exposed to the fluid environment of use prior to delivery, said system comprising:
(a) a piston that divides the system into a first and second chamber, the first and second chambers each having an open end;
(b) a water-swellable agent formulation in the first chamber;
(c) an active agent formulation in the second chamber;
(d) a semipermeable plug in the open end of the first chamber; and
(e) a back-diffusion regulating outlet in the open end of the second chamber;
wherein said system effectively seals and isolates the active agent chamber from the environment of use.
11. The system of
12. The system of
13. The system of
14. The system of
15. The system of
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19. The system of
20. An implantable active agent delivery system for delivering an active agent to a fluid environment of use at a steady state flow rate of at least 70% of an intended flow rate after start-up, said agent being susceptible to degradation if exposed to the fluid environment of use prior to delivery, said system comprising:
(a) a piston that divides the system into a first and second chamber, the first and second chambers each having an open end;
(b) a water-swellable agent formulation in the first chamber;
(c) an active agent formulation in the second chamber;
(d) a semipermeable plug in the open end of the first chamber; and
(e) a back-diffusion regulating outlet in the open end of the second chamber;
wherein said system effectively seals and isolates the active agent chamber from the environment of use.
This application is a continuation of application Ser. No. 09/848,211, filed on May 4, 2001; U.S. Pat. No. 6,395,292 B2 which is a continuation of application Ser. No. 09/366,746, filed on Aug. 4, 1999; U.S. Pat. No. 6,261,584 B1 which is a continuation of application Ser. No. 08/943,007, filed on Oct. 2, 1997; U.S. Pat. No. 5,985,305 which is a continuation of application Ser. No. 08/791,699, filed on Jan. 30, 1997 U.S. Pat. No. 5,728,396.
This application is a continuation-in-part application of a provisional application (Ser. No. 60/122,056) which was filed an Feb. 2, 1996 as regular U.S. application Ser. No. 08/595,761 and converted to a provisional application via a petition filed on Jan. 21, 1997.
This invention is related to the sustained delivery of a biologically active agent. More particularly, the invention is directed to an implantable delivery system for the prolonged delivery of an active agent to a fluid environment in a natural or artificial body cavity.
Treatment of disease by prolonged delivery of an active agent at a controlled rate has been a goal in the drug delivery field. Various approaches have been taken toward delivering the active agents.
One approach involves the use of implantable diffusional systems. For example, subdermal implants for contraception are described by Philip D. Darney in Current Opinion in Obstetrics and Gynecology 1991, 3:470-476. Norplant� requires the placement of 6 levonorgestrel-filled silastic capsules under the skin. Protection from conception for up to 5 years is achieved. The implants operate by simple diffusion, that is, the active agent diffuses through the polymeric material at a rate that is controlled by the characteristics of the active agent formulation and the polymeric material. Darney further describes biodegradable implants, namely Capranar™ and norethindrone pellets. These systems are designed to deliver contraceptives for about one year and then dissolve. The Capranor™ systems consist of poly(ε-caprolactone) capsules that are filled with levonorgestrel and the pellets are 10% pure cholesterol with 90% norethindrone. Implantable infusion pumps have also been described for delivering drugs by intravenous, intra-arterial, intrathecal, intraperitoneal, intraspinal and epidural pathways. The pumps are usually surgically inserted into a a subcutaneous pocket of tissue in the lower abdomen. System's for pain management, chemotherapy and insulin delivery are described in the BBI Newsletter, Vol. 17, No. 12, pages 209-211, December 1994. These systems provide for more accurately controlled delivery than simple diffusional systems.
One particularly promising approach involves osmotically driven devices such as those described in U.S. Pat. Nos. 3,987,790, 4,865,845, 5,057,318, 5,059,423, 5,112,614, 5,137,727, 5,234,692 and 5,234,693 which are incorporated by reference herein. These devices can be implanted into an animal to release the active agent in a controlled manner for a predetermined administration period. In general, these devices operate by imbibing fluid from the outside environment and releasing corresponding amounts of the active agent.
The above-described devices have been useful for delivering active agents to a fluid environment of use. Although these devices have found application for human and veterinary purposes, there remains a need for devices that are capable of delivering active agents, particularly potent unstable agents, reliably to a human being at a controlled rate over a prolonged period of time.
Implantable osmotic systems for delivery of an active agent to an animal are well known. Adaptation of these systems for human use raises a number of difficult issues. The size of the device may need to be decreased for human implantation. The strength of the device must be sufficient to ensure a robust system. Accurate and reproducible delivery rates and durations must be ensured and the period from implantation to start-up of delivery must be minimized. The active agent must return its purity and activity for extended periods of time at the elevated temperatures encountered in the body cavity.
Accordingly, in one aspect, the invention is a fluid-imbibing device for g delivering an active agent formulation to a fluid environment of use. The device comprises a water-swellable, semipermeable material that is received in sealing relationship with the interior surface at one end of an impermeable reservoir. The device further contains an active agent to be displaced from the device-when the water-swellable material swells.
In another aspect, the invention is directed to an implantable device for delivering an active agent to a fluid environment of use. The device comprises a reservoir and a back diffusion regulating outlet in a mating relationship. The flow path of the active agent comprises a pathway formed between the mating surfaces of the back diffusion regulating outlet and the reservoir.
In yet another aspect, the present invention is directed to a device for storing an active agent in a fluid environment of use during a predetermined administration period, the device comprising a reservoir containing an active agent The reservoir is impermeable and formed at least in part from a metallic material. The portion of the reservoir contacting the active agent is non-reactive with the active agent, and is formed of a material selected from the group consisting of titanium and its alloys.
In a further aspect, the invention is an implantable fluid-imbibing active agent delivery system that comprises an impermeable reservoir. The reservoir contains a piston that divides the reservoir into an active agent containing chamber and a water-swellable agent containing chamber. The active agent containing chamber is provided with a back-diffusion regulating outlet. The water-swellable agent containing chamber is provided with a semipermeable plug. Either the plug or the outlet is releasable from the reservoir at an internal pressure that is lower than the maximum osmotic pressure generated by the water-swellable agent.
The invention is further directed to a fluid-imbibing implantable active agent delivery system where the time to start-up of delivery is less than 10% of the predetermined administration period.
In another aspect, the invention is directed to a method for preparing a fluid-imbibing implantable active agent delivery system. The method comprises injection molding a semipermeable plug into the end of an impermeable reservoir such that the plug is protected by the reservoir.
In still another aspect, the invention is directed to an impermeable active agent delivery system for delivering an active agent that is susceptible to degradation. The reservoir contains a piston that divides the reservoir into a water-swellable agent chamber and an active agent chamber. The open end of the water-swellable agent chamber contains a semipermeable membrane and the open end of the active agent chamber contains a back-diffusion regulating outlet. The system effectively seals the active agent chamber and isolates it from the environment of use.
In a further aspect, the invention is directed to a back-diffusion regulating outlet useful in an active agent delivery system. The outlet defines a flow path wherein the length, interior cross-sectional shape and area provide for an average linear velocity of active agent that is higher than the linear inward flow of fluid in the environment of use.
The invention is also directed to a semipermeable plug useful in an active agent delivery system. The plug is water-swellable and must expand linearly in the delivery system to commence pumping upon insertion of the system into the fluid environment of use.
The invention is further directed to implantable delivery systems useful for delivering leuprolide.
The figures are not drawn to scale, but are set forth to illustrate various embodiments of the invention. Like numbers refer to like structures.
FIGS. 1 and 2 are partial cross-sectional views of two embodiments of the delivery device of the invention.
FIG. 3 is an enlarged cross-sectional view of the back-diffusion regulating outlet of FIG. 1.
FIG. 4 is a graph that shows the effect of orifice diameter and length on drug diffusion.
FIGS. 5, 6, 7 and 8 are enlarged cross-sectional views of further embodiments of the semipermeable plug end of the reservoir according to the invention.
FIGS. 9, 10 and 11 are graphs of release rates for systems with leuprolide (FIG. 9) and with blue dye and with different membranes (FIGS. 10 and 11).
The present invention provides a device for the delivery of an active agent to a fluid environment of use in which the active agent must be protected from the fluid environment until it is delivered. Prolonged and controlled delivery is achieved.
The term "active agent" intends the active agent(s) optionally in combination with pharmaceutically acceptable carriers and, optionally additional ingredients such as antioxidants, stabilizing agents, permeation enhancers, etc.
By a "predetermined administration period" is intended a period of greater than 7 days, often between about 30 days and 2 years, preferably greater than about 1 month and usually between about 1 month and 12 months.
By the time to "start-up" of delivery is intended the time from insertion into the fluid environment of use until the active agent is actually delivered at a rate not less than approximately 70% of the intended steady-state rate.
The term "impermeable" intends that the material is sufficiently impermeable to environmental fluids as well as ingredients contained within the dispensing device such that the migration of such materials into or out of the device through the impermeable device is-so low as to have substantially no adverse impact on the function of the device during the delivery period.
The term "semipermeable" intends that the material is permeable to external fluids but substantially impermeable to other ingredients contained is within the dispensing device and the environment of use.
As used herein, the terms "therapeutically effective amount" or "therapeutically effective rate" refer to the amount or rate of the active agent needed to effect the desired biologic or pharmacologic effect.
The active agent delivery devices of the invention find use where the prolonged and controlled delivery of an active agent is desired. In many cases the active agent is susceptible to degradation if exposed to the environment of use prior to delivery and the delivery devices protect the agent from such exposure.
FIG. 1 shows one embodiment of the device according to the invention. In FIG. 1 a fluid-imbibing system 10 is shown that comprises an impermeable reservoir 12. The reservoir 12 is divided into two chambers by a piston 16. The first chamber 18 is adapted to contain an active agent and the second chamber 20 is adapted to contain a fluid-imbibing agent. A back-diffusion regulating outlet 22 is inserted into the open end of the first compartment 18 and a water-swellable semipermeable plug 24 is inserted into the open end of the second chamber 20. In FIG. 1, the back-diffusion regulating outlet 22 is shown as a male threaded member in a mating relationship with the smooth interior surface of the reservoir 12 thereby forming therebetween helical flow path 34. The pitch (x), the amplitude (y), and the cross-sectional area and shape of the helical path 34 formed between the mating surfaces of the back-diffusion regulating outlet 22 and the reservoir 12 as shown in FIG. 3 are factors that affect both the efficiency of path 34 preventing back-diffusion of external fluid into the formulation in chamber 18 and the back pressure in the device. The geometry of outlet 22 prevents water diffusion into the reservoir. In general, it is desired that these characteristics be selected so that the length of the helical flow path 34 and the velocity of flow of active agent therethrough is sufficient to prevent back-diffusion of external fluid through the flow path 34 without significantly increasing the back pressure, so that, following start-up, the release rate of the active agent is governed by the osmotic pumping rate.
FIG. 2 is a second embodiment of the device of the invention with a reservoir 12, piston 16 and plug 26. In this embodiment, the flow path 36 is formed between a threaded back-diffusion regulating outlet 40 and threads 38 formed on the interior surface of the reservoir 12. The amplitudes of the threaded portions of the back-diffusion regulating outlet 40 and reservoir 12 are different so that a flow path 36 is formed between the reservoir 12 and the back-diffusion regulating outlet 40.
The water-swellable semipermeable plugs 24 and 26 shown in FIGS. 1 and 2 respectively are inserted into the reservoir such that the reservoir wall concentrically surrounds and protects the plug. In FIG. 1, the top portion 50 of the plug 24 is exposed to the environment of use and may form a flanged end cap portion 56 overlaying the end of reservoir 12. The semipermeable plug 24 is resiliently engaged with the interior surface of the reservoir 12 and in FIG. 1 is shown to have ridges 60 that serve to frictionally engage the semipermeable plug 24 with the interior of reservoir 12. In addition, the ridges 60 serve to produce redundant circumferential seals that function before the semipermeable plug 24 expands due to hydration. The clearance between ridges 60 and the interior surface of the reservoir 12 prevents hydration swelling from exerting stresses on the reservoir 12 that can result in tensile failure of the reservoir 12 or compression or shear failure of the plug 24. FIG. 2 shows a second embodiment of the semipermeable plug 26 where the plug is injection molded into the top portion of the reservoir and where the top of the semipermeable plug 26 is flush with the top 62 of the reservoir 12. In this embodiment, the diameter of the plug is substantially less than the diameter of the reservoir 12. In both embodiments the plugs 24 and 26 will 9 swell upon exposure to the fluid in body cavity forming an even tighter seal to with the reservoir 12.
The novel configurations of the components of the above-described embodiments provide for implantable devices that are uniquely suited for implantation into humans and can provide delivery devices which are capable of storing unstable formulations at body temperatures for extended periods of time, which devices have start-up times of less than 10% of the administration period and can be designed to be highly reliable and with predictable fail safe modes.
Reservoir 12 must be sufficiently strong to ensure that it will not leak, crack, break or distort so as to expel its active agent contents under stresses it would be subjected to during use while being impermeable. In particular, it should be designed to withstand the maximum osmotic pressure that could be generated by the water-swellable material in chamber 20. Reservoir 12 must also be chemically inert and biocompatible, that is, it must be non-reactive with the active agent formulation as well as the body. Suitable materials generally comprise a non-reactive polymer or a biocompatible metal or alloy. The polymers include acrylonitrile polymers such as acrylonitrile-butadiene-styrene terpolymer, and the like; halogenated polymers such as polytetrafluorcethylene, polychiorotrifluoroethylene, copolymer tetrafluoroethylene and hexafluoropropylene; polyimide; polysulfone; polycarbonate; polyethylene; polypropylene; polyvinylchloride-acrylic copolymer; polycarbonate-acrylanitrile-butadiene-styrene; polystyrene; and the like. The water vapor transmission rate through compositions useful for forming the reservoir are reported in J. Pharm. Sci., Vol. 29, pp. 1634-37 (1970), Ind. Eng. Chem., Vol. 45, pp. 2296-2306 (1953); Materials Engineering, Vol. 5, pp. 3845 (1972); Ann. Book of ASTM Stds., Vol. 8.02, pp. 208-211 and pp. 584-587 (1984); and Ind. and Eng. Chem., Vol. 49, pp. 1933-1936 (1957). The polymers are known in the Handbook of Common Polymers by Scott and Roff, CRC Press, Cleveland Rubber Co., Cleveland, Ohio. Metallic materials useful in the invention include stainless steel, titanium, platinum, tantalum, gold and their alloys as well as gold-plated ferrous alloys, la platinum-plated ferrous alloys, cobalt-chromium alloys and titanium nitride coated stainless steel. A reservoir made from titanium or a titanium alloy having greater than 60%, often greater than 85% titanium is particularly preferred for the most size-critical applications, for high payload capability and for long duration applications and for those applications where the formulation is sensitive to body chemistry at the implantation site or where the body is sensitive to the formulation. Preferred systems maintain at least 70% active agent after 14 months at 37� C. and have a shelf stability of at least about 9 months, or more preferably at least about two years, at 2-8� C. Most preferably, systems may be stored at room temperature. In certain embodiments, and for applications other than the fluid-imbibing devices specifically described, where unstable formulations are in chamber 18, particularly protein and/or peptide formulations, the metallic components to which the formulation is exposed must be formed of titanium or its alloys as described above.
The devices of this invention provide a sealed chamber 18 which effectively isolates the formulation from the fluid environment. The reservoir 12 is made of a rigid, impermeable and strong material. The water-swellable semipermeable plug 24 is of a lower durometer material and will conform to the shape of the reservoir to produce a liquid-tight seal with the interior of reservoir 12 upon wetting. The flow path 34 isolates chamber 18 from back-diffusion of environmental fluid. Piston 16 isolates chamber 18 from the environmental fluids that are permitted to enter chamber 20 through semipermeable plugs 24 and 26 such that, in use at steady-state flow, active agent is expelled through outlet 22 at a rate corresponding to the rate at which water from the environment flows into the water-swellable material in chamber 20 through semipermeable plugs 24 and 26. As a result, the plug and the active agent formulation will be protected from damage and their functionality will not be compromised even if the reservoir is deformed. In addition, the use of sealants and adhesives will be avoided and the attendant issues of biocompatibility and ease of manufacture resolved.
Materials from which the semipermeable plug are made are those that are semipermeable and that can conform to the shape of the reservoir upon wetting and adhere to the rigid surface of the reservoir. The semipermeable plug expands as it hydrates when placed in a fluid environment so that a seal is generated between the mating surfaces of the plug and the reservoir. The strength of the seals between the reservoir 12 and the outlet 22 and the reservoir 12 and the plugs 24 and 26 can be designed to withstand the maximum osmotic pressure generated by the device. In a preferred alternative, the plugs 24 and 26 may be designed to withstand at least 10� the osmotic agent compartment 20 operating pressure. In a further alternative the plugs 24 and 26 may be releasable from the reservoir at an internal pressure that is lower than the pressure needed to release the back diffusion regulating outlet. In this fail safe embodiment, the water-swellable agent chamber will be opened and depressurized, thus avoiding dispelling the diffusion regulating outlet and attendant release of a large quantity of the active agent. In other cases, where a fail-safe system requires the release of the active agent formulation rather than the water-swellable agent formulation, the semipermeable plug must be releasable at a pressure that is higher than the outlet.
In either case, the semipermeable plug must be long enough to sealably engage the reservoir wall under the operating conditions, that is, it should have an aspect ratio of between 1:10 and 10:1 length to diameter, preferably at least about 1:2 length to diameter, and often between 7:10 and 2:1. The plug must be able to imbibe between about 0.1% and 200% by weight of water. The diameter of the plug is such that it will sealingly fit inside the reservoir prior to hydration as a result of sealing contact at one or more circumferential zones and will expand in place upon wetting to form an even tighter seal with the reservoir. The polymeric materials from which the semipermeable plug may be made vary based on the pumping rates and a device configuration requirements and include but are not limited to plasticized cellulosic materials, enhanced polymethylmethacrylate such as hydroxyethylmethacrylate (HEMA) and elastomeric materials such as polyurethanes and polyamides, polyether-polyamide copolymers, thermoplastic copolyesters and the like.
The piston 16 isolates the water-swellable agent in chamber 20 from the active agent in chamber 18 and must be capable of sealably moving under pressure within reservoir 12. The piston 16 is preferably made of a material that is of lower durometer than the reservoir 12 and that will deform to fit the lumen of the reservoir to provide a fluid-tight compression seal with the reservoir 12. The materials from which the piston are made are preferably elastomeric materials that are impermeable and include but are not limited to polypropylene, rubbers such as EPOM, silicone rubber, butyl rubber, and the like, and thermoplastic elastomers such as plasticized polyvinylchloride, polyurethanes, Santoprene�, C-Flex� TPE (Consolidated Polymer Technologies Inc.), and the like. The piston may be of a self-loading or compression-loaded design.
The back-diffusion regulating outlet 22 forms the delivery pathway through which the active agent flows from the chamber 18 to the implantation site where absorption of the active agent takes place. The seal between the outlet 22 and the reservoir 12 can be designed to withstand the maximum osmotic pressure generated within the device or to fail-safe in the modes described above. In a preferred embodiment, the pressure required to release back-diffusion regulating outlet 22 is at least 10� the pressure required to move piston 16 and/or at least 10� the pressure in chamber 18.
The exit flow path of the active agent is the pathway 34 formed between the mating surfaces of the back-diffusion regulating outlet 22 and the reservoir 12. The pathway length, interior cross-sectional shape and area of the outlet path 34 or 36 are chosen such that the average linear velocity of the exiting active agent is higher than that of the linear inward flux of materials in the environment of use due to diffusion or osmosis, thereby attenuating or moderating back-diffusion and its deleterious effects of contaminating the interior of the pump, destabilizing, diluting, or otherwise altering the formulation. The release rate of active agent can be modified by modifying the outlet pathway geometry, which relationship is shown below.
The convective flow of active agent out of outlet 22 is set by the pumping rate of the system and the concentration of active agent in chamber 20 and can be represented as follows:
Qca is the convective transport of agent A in mg/day
Q is the overall convective transport of the agent and its diluents in cm3/day
Ca is the concentration of agent A in the formulation within chamber 20 in mg/cm3
The diffusive flow of agent A through the material in the outlet 22 is a function of agent concentration, cross-sectional configuration of flow path 34 or 36, agent diffusivity and length of flow path 34 or 36, and can be 76 represented as follows:
Qda is the diffusive transport of agent A in mg/day
D is the diffusivity through the material in path 34 or 36 in cm2/day
r is the effective inner radius of the flow path in cm
ΔCa is the difference between the concentration of agent A in the reservoir and in the body outside of the outlet 22 in mg/cm3
L is the length of the flow path in cm
In general, the concentration of agent in the reservoir is much greater than the concentration of agent in the body outside of the orifice such that the difference, ΔCa can be approximated by the concentration of agent within the reservoir, Ca.
It is generally desirable to keep the diffusive flux of agent at less than 10% of the convective flow. This is represented as follows:
Equation 4 indicates that the relative diffusive flux decreases with increasing volumetric flow rate and path length and increases with increasing diffusivity and channel radius and is independent of drug concentration. Equation 4 is plotted in FIG. 4 as a function of length (L) and diameter (d) for D=2�10−6 cm2/sec and Q=0.36 μl/day.
The diffusive flux of water where the orifice opens into chamber 18 can be approximated as:
Co is the concentration profile of water in mg/cm3
Q is the mass flow rate in mg/day
L is the length of the flow path in cm
Dw is the diffusivity of water through the material in the flow path in cm2/day
A is the cross-sectional area of the flow path in cm2
The hydrodynamic pressure drop across the orifice can be calculated as follows:
Simultaneously solving equations (4), (5) and (6) gives the values shown in Table 1 where:
Q=0.38 μl/day
Ca=0.4 mg/μl
L=5 cm
Da=2.00 E−06 cm2/sec
μ=5.00E+02 cp
Cw0=0 mg/μl
Dw=6.00 E+06 cm2 sec
The calculations indicate that an orifice diameter of between about 3 and 10 mil and a length of 2 to 7 cm is optimal for a device with the operating conditions described. In a preferred embodiment, the pressure drop across the orifice is less than 10% of the pressure required to release the back-diffusion regulating outlet 22.
The back-diffusion regulating outlet 22 preferably forms a helical pathway 34 or 36 incorporating a long flow path with a means of mechanically attaching the outlet into the reservoir without using adhesives or other sealants. The back-diffusion regulating outlet is made of an inert and biocampatible material selected from but not limited to metals including but not limited to titanium, stainless steel, platinum and their alloys and cobalt-chromium alloys and the like, and polymers including but not limited to polyethylene, polypropylene, polycarbonate and polymethylmethacrylate and the like. The flow path is usually between about 0.5 and 20 cm long, preferably between about 1 and 10 cm long and between about 0.001 and 0.020 inches in diameter, preferably between about 0.003 and 0.015 inches to allow for a flow of between about 0.02 and 50 μl/day, usually 0.2 to 10 μl/day and often 0.2 to 2.0 μl/day. Additionally, a catheter or other system may be attached to the end of the back-diffusion regulating outlet to provide for delivery of the active agent formulation at a site removed from the implant. Such systems are known in the art and are described, for example, in U.S. Pat. Nos. 3,732,865 and 4,340,054 which are incorporated herein by reference. Further, the flow path design may be useful in systems other than the fluid-imbibing devices specifically described herein.
The inventive device configurations described above also allow for a minimal period of delay from start-up to steady-state flow rate. This is accomplished in part as a result of the configuration of the semipermeable plug 24 or 26. As water is imbibed by the semipermeable plug, it swells. Radial expansion is limited by the rigid reservoir 12, thus the expansion must occur linearly, thereby pushing against the water-swellable agent in chamber 18, which in turn pushes against the piston 16. This allows pumping to commence prior to the time that water reaches the water-swellable agent which otherwise would be required before pumping could commence. To facilitate reliable start-up, the flow path 34 can be precharged with the active agent in chamber 18. Further, the geometry of the outlet 22 allows for initial delivery that is influenced by the concentration gradient of drug along the length of the outlet. The start-up period is less than about 25% of the predetermined delivery period and is often less than about 10% and usually less than about 5% of the predetermined delivery period. In a preferred embodiment for a one year system, at least 70% of the steady-state flow rate is achieved by day 14.
The water-swellable agent formulation in chamber 20 is preferably a tissue tolerable formulation whose high osmotic pressure and high solubility *a propels the active agent over a long period of time while remaining in saturated solution in the water admitted by the semipermeable membrane. The water-swellable agent is preferably selected for tolerability by subcutaneous tissue, at least at pumping rates and hypothetically resulting concentrations to allow inadvertent dispensing from implanted devices left in the patient for a longer than labeled period. In preferred embodiments, the water-swellable agent should not diffuse or permeate through the semipermeable plug 24 or 26 to any appreciable amount (e.g., less than 8%) under normal operating conditions. Osmotic agents, such as NaCl with appropriate tabletting agents (lubricants and binders) and viscosity modifying agents, such as sodium carboxymethylcellulose or sodium polyacrylate are preferred water-swellable agents. Other osmotic agents useful as the water-swellable agent include osmopolymers and osmagents and are described, for example, in U.S. Pat. No. 5,413,572 which is incorporated by reference herein. The water-swellable agent formulation can be a slurry, a tablet, a molded or extruded material or other form known in the art. A liquid or gel additive or filler may be added to chamber 20 to exclude air from spaces around the osmotic engine. Exclusion of air from the devices should mean that delivery rates will be less affected by nominal external pressure changes (e.g.,�7 p.s.i. (�5 a.t.m.)).
The devices of the invention are useful to deliver a wide variety of active agents. These agents include but are not limited to pharmacologically active peptides and proteins, genes and gene products, other gene therapy agents, and other small molecules. The polypeptides may include but are not limited to growth hormone, somatotropin analogues, somatomedin-C, Gonadotropic releasing hormone, follicle stimulating hormone, luteinizing hormone, LHRH, LHRH analogues such as leuprolide, nafarelin and goserelin, LHRH agonists and antagonists, growth hormone releasing factor, calcitonin, colchicine, gonadotropins such as chorionic gonadotropin, oxytocin, octreotide, somatotropin plus an amino acid, vasopressin, adrenocorticotrophic hormone, epidermal growth factor, prolactin, somatostatin, somatotropin plus a protein, cosyntropin, lypressin, polypeptides such as thyrotropin releasing hormone, thyroid stimulation hormone, secretin, pancreozymin, enkephalin, glucagon, endocrine agents secreted internally and distributed by way of the bloodstream, and the like. Further agents that may be delivered include α1 antitrypsin, factor VII, factor IX and other coagulation factors, insulin and other peptide hormones, adrenal cortical stimulating hormone, thyroid stimulating hormone and other pituitary hormones, interferon α, β, and δ, erythropoietin, growth factors such as GCSF, GMCSF, insulin-like growth factor 1, tissue plasminogen activator, CD4, dDAVP, interieukin-1 receptor antagonist, tumor necrosis factor, pancreatic enzymes, lactase, cytokines, interleukin-1 receptor antagonist, interleukin-2, tumor necrosis factor receptor, tumor suppresser proteins, cytotaxic proteins, and recombinant antibodies and antibody fragments, and the like.
The above agents are useful for the treatment of a variety of conditions including but not limited to hemophilia and other blood disorders, growth disorders, diabetes, leukemia, hepatitis, renal failure, HIV infection, hereditary diseases such as cerbrosidase deficiency and adenosine deaminase deficiency, hypertension, septic shock, autoimmune diseases such as multiple sclerosis, Graves disease, systemic lupus erythematosus and rheumatoid arthritis, shock and wasting disorders, cystic fibrosis, lactose intolerance, Crohn's diseases, inflammatory bowel disease, gastrointestinal and other cancers.
The active agents may be anhydrous or aqueous solutions, suspensions or complexes with pharmaceutically acceptable vehicles or carriers such that a flowable formulation is produced that may be stored for long periods on the shelf or under refrigeration, as well as stored in an implanted delivery system. The formulations may include pharmaceutically acceptable carriers and additional inert ingredients. The active agents may be in various forms, such as uncharged molecules, components of molecular complexes or pharmacologically acceptable salts. Also, simple derivatives of the agents (such as prodrugs, ethers, esters, amides, etc.) which are easily hydrolyzed by body pH, enzymes, etc., can be employed.
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" in no way excludes the use of two or more such agents. 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 any subcutaneous position or body cavity, such as the peritoneum or uterus, and may or may not be equivalent to the point of ultimate delivery of the active agent formulation. A single dispensing device or several dispensing devices can be administered to a subject during a therapeutic program. The devices are designed to remain implanted during a predetermined administration period. If the devices are not removed following the administration, they may be designed to withstand the maximum osmotic pressure of the water-swellable agent or they may be designed with a bypass to release the pressure generated within the device.
The devices of the present invention are preferably rendered sterile prior to use, especially when such use is implantation. This may be accomplished by separately sterilizing each component, e.g., by gamma radiation, steam sterilization or sterile filtration, then aseptically assembling the final system. Alternatively, the devices may be assembled, then terminally sterilized using any appropriate method.
Reservoir 12 is prepared preferably by machining a metal rod or by extrusion or injection molding a polymer. The top portion of the reservoir may a be open as shown in FIG. 1 or may contain a cavity as shown in FIG. 2.
Where the reservoir 12 is open as shown in FIG. 1, a water-swellable semipermeable plug 24 is inserted mechanically from the outside of the reservoir without using an adhesive before or after insertion of the piston and water-swellable agent formulation. Reservoir 12 may be provided with grooves or threads which engage ribs or threads on plug 24.
Where the reservoir 12 contains a cavity as shown in FIG. 2, the cavity may be cylindrical in shape, as shown in FIG. 5, it may be stepped, as shown in FIG. 6, it may be helical, as shown in FIG. 7 or it may be in a spaced configuration, as shown in FIG. 8. The semipermeable plug 26 is then injected, inserted, or otherwise assembled into the cavity so that it forms a seal with the reservoir wall.
Following insertion of the plug 26 either mechanically, by welding or by injection, the water-swellable agent is assembled into the reservoir followed by insertion of the piston, with appropriate steps taken to vent entrapped air. The active agent is filled into the device using a syringe or a precision dispensing pump. The diffusion moderator is inserted into the device, usually by a rotating or helical action, or by axial pressing.
The following examples are illustrative of the present invention. They are not to be construed as limiting the scope of the invention. Variations and equivalents of these examples will be apparent to those of skill in the art in light of the present disclosure, the drawings and claims herein.
A system containing leuprolide acetate for the treatment of prostate cancer was assembled from the following components:
Reservoir (HDPE) (5 mm outside diameter, 3 mm inside diameter)
Piston (Santoprene�)
Lubricant (silicone medical fluid)
Compressed osmotic engine (60% NaCl, 40% sodium carboxymethyl cellulose)
Membrane plug (Hytrel polyether-ester block copolymer, injection molded to desired shape)
Back diffusion Regulating Outlet (polycarbonate)
Active agent (0.78 g of 60% propylene glycol and 40% leuprolide acetate)
The piston and inner diameter of the reservoir were lightly lubricated with silicon medical fluid. The piston 16 was inserted into the open end of chamber 20. Two osmotic engine tablets (40 mg each) were then inserted on top of piston 16. After insertion, the osmotic engine was flush with the end of the reservoir. The membrane plug 24 was inserted by lining up the plug with the reservoir and pushing gently until the plug was fully engaged in the reservoir. Active agent was loaded into a syringe which was then used to fill chamber 18 from its open end by injecting the material into the open tube until the formulation was ˜3 mm from the end. The filled reservoir was centrifuged (outlet end "up") to remove any air bubbles that have been trapped in the formulation during filling. The outlet 22 was screwed into the open end of the reservoir until completely engaged. As the outlet was screwed in, excess formulation exited out of the orifice ensuring a uniform fill.
Insertion of the device of Example 1 is done under aseptic conditions using a trocar similar to that used in the implantation of Norplant� contraceptive implants to position the device under the skin. The insertion area is typically in the inside of-the upper arm, 8 to 10 cm above the elbow.
The area is anesthetized and an incision is made through the skin. The incision is approximately 4 mm long. The trocar is inserted into the incision until the tip of the trocar is at a distance of 4 to 6 cm from the incision. The obturator is then removed from the trocar and the device of Example 1 inserted into the trocar. The device is then advanced to the open end of the trocar using the obturator. The obturator is then held in position, thus immobilizing the device of Example 1 while the trocar is withdrawn over both the device and the obturator. The obturator is then removed, leaving the implant behind in a well-controlled position. The edges of the incision are then secured with a skin closure. The area is covered and kept dry for 2 to 3 days.
The device of Example 1 is removed as follows: The device is located by fingertip palpation of the upper arm area. The area at one end of the implant is then anesthetized and an approximately 4 mm, perpendicular incision is made through the skin and any fibrous capsule tissue surrounding the implant area. The end of the device opposite the incision is pushed so that the device end proximal to the incision is urged out of the incision. Any further fibrotic tissue is cut with a scalpel. Following removal, the procedure of Example 2 can be followed to insert a new device.
Glass test tubes were filled with 35 ml distilled water and then placed in a 37� C. water bath. A single device as described in Example 1 was placed in each test tube and the test tubes were changed periodically. The delivery rate profile from the system is shown in FIG. 9. The system does not have any start-up time because the system exhibits a period of initial high release followed by a lower steady state release for a period of 200 days.
Glass test tubes were filled with 35 ml distilled water which were then placed in a 37� C. water bath. After the test tubes had come up to temperature, a single device as described in Example 1, but with membrane materials described below and containing 1% FD&C blue dye in water as the 16 drug formulation, was placed in each tube. Water from the test tube permeated through the membrane causing the system to pump formulation (blue dye) into the surrounding water in the test tube. At regular intervals, systems were switched to fresh test tubes. The amount of dye released was determined by measuring the concentration of blue dye in each test tube using a spectrophotometer. The pumping rate was calculated from the total dye released, the volume of water in the tube, the initial concentration of dye and the interval over which the system was in the test tube. Results for two different tests are shown in FIGS. 10 and 11. FIG. 10 shows 3 different systems with different plug materials (Hytret� 2, 3 and 12 month systems) and FIG. 11 shows 4 systems with different plug materials. These materials are:
The systems were capable of delivering for a period of from 2 to 12 months, depending on the membrane used.
A system containing leuprolide acetate for the treatment of prostate cancer was assembled from the following components:
a Reservoir (Titanium, Ti6Al4V alloy) (4 mm outside diameter, 3 mm inside diameter)
Piston (C-Flex�)
Lubricant (silicone medical fluid)
Compressed osmotic engine (76.4% NaCl, 15.5% sodium carboxymethyl cellulose, 6% povidone, 0.5% Mg Stearate, 1.6% water)
PEG 400 (8 mg added to osmotic engine to fill air spaces)
Membrane plug (polyurethane polymer, injection molded to desired shape)
Back diffusion Regulating Outlet (polyethylene)
Drug formulation (0.150 g of 60% water and 40% leuprolide acetate)
The piston and inner diameter of the reservoir were lightly lubricated. The piston was inserted ˜0.5 cm into the reservoir at the membrane end. PEG 400 was added into the reservoir. Two osmotic engine tablets (40 mg each) were then inserted into the reservoir from the membrane end. After insertion, the osmotic engine was flush with the end of the reservoir. The membrane plug was inserted by lining up the plug with the reservoir and pushing gently until the retaining features of the plug were fully engaged in the reservoir. Formulation was loaded into a syringe which was then used to fill the reservoir from the outlet end by injecting formulation into the open tube until the formulation was ˜3 mm from the end. The filled reservoir was centrifuged (outlet end "up") to remove any air bubbles that have been trapped in the formulation during filling. The outlet was screwed into the open end of the reservoir until completely engaged. As the outlet was screwed in, excess formulation exited out of the orifice ensuring a uniform fill.
A system containing leuprolide acetate for the treatment of prostate cancer was assembled from the following components:
Reservoir (Titanium Ti6Al4V alloy) (4 mm outside diameter, 3 mm inside diameter, 4.5 cm length)
Piston (C-Fiex� TPE elastomer, available from Consolidated Polymer Technologies, Inc.)
Lubricant (silicone medical fluid 360)
Compressed osmotic engine tablet (76.4% NaCl, 15.5% sodium carboxymethyl cellulose, 6% povidone, 0.5% Mg Stearate, 1.5% water, 50 mg total)
PEG 400 (8 mg added to osmotic engine to fill air spaces)
Membrane plug (polyurethane polymer 20% water uptake, injection molded to desired shape 3 mm diameter�4 mm length)
Back-diffusion Regulating Outlet (polyethylene, with 6 mil�5 cm channel)
Drug formulation (leuprolide acetate dissolved in DMSO to a measured content of 65 mg leuprolide)
Systems were assembled as in Example 6, using aseptic procedures to assemble y-irradiated subassemblies and filled aseptically with sterile filtered leuprolide DMSO formulation.
Release Rate
These systems delivered about 0.35 μL/day leuprolide formulation containing on average 150 μg leuprolide in the amount delivered per day. They provide delivery of leuprolide at this rate for at least one year. The systems achieved approximately 70% steady-state delivery by day 14.
Implantation and Removal
Systems will be implanted under local anesthetic and by means of an incision and trocar as in Example 2 to patient suffering from advanced prostatic cancer.
After one year, systems will be removed under local anesthetic as described in Example 3. New systems may be inserted at that time.
Leuprolide acetate, an LHRH agonist, acts as a potent inhibitor of gonadotropin secretion when given continuously and in therapeutic doses. Animal and human studies indicate that following an initial stimulation, chronic administration of leuprolide acetate results in suppression of testicular steroidogenesis. This effect is reversible upon discontinuation of drug therapy. Administration of leuprolide acetate has resulted in inhibition of the growth of certain hormone-dependent tumors (prostatic tumors in Noble and Dunning male rats and DMBA-induced mammary tumors in female rats) as well as atrophy of the reproductive organs. In humans, administration of leuprolide acetate results in an initial increase in circulating levels of luteinizing hormone (LH) and follicle stimulating hormone (FSH), leading to a transient increase in levels of the gonadal steroids (testosterone and dihydrotestosterone in males). However, continuous administration of leuprolide acetate results in decreased level of LH and FSH. In males, testosterone is reduced to castrate levels. These decreases occur within two to six weeks after initiation of treatment, and castrate levels of testosterone in prostatic cancer patients have been demonstrated for multiyear periods. Leuprolide acetate is not active when given orally.
Systems will be prepared as in Example 7, then inserted as described. The continuous administration of leuprolide for one year using these systems will reduce testosterone to castrate levels.
The above description has been given for ease of understanding only. No unnecessary limitations should be understood therefrom, as modifications s will be obvious to those skilled in the art.
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UGA Career: Batted .295-16-101 with 24 stolen bases in 224 games including 211 starts.
*A 19th round pick of the Atlanta Braves in the 2012 MLB draft
2012 (Senior): Appeared in 57 games with 52 starts (49-2B, 2-3B, 1-SS) as team went 31-26
*Ended career ranked fifth in school history with 224 games played including 211 starts
*Batted .250 with two home runs and 26 RBI overall and .265-1-12 in SEC action
*Ended season on an eight-game hitting streak including hitting .462 (6-13) in the Alabama series
*Went 3-for-4 with a home run and 3 RBI in win over Tennessee on March 17
*Posted a .981 fielding percentage in 261 total chances (96 putouts, 160 assists, 5 errors) at second base and helped turn 33 double plays, also was perfect in two starts at third bases and one start at shortstop in a total of 13 chances
*Named to 2012 UGA Athletic Director's Academic Honor Roll and to SEC Academic Honor Roll
2011 (Junior): Appeared in all 65 games with 64 starts at second base in helping team go 33-32 and reach the NCAA Corvallis Regional Final
*Batted a team-best .332 with five home runs and 38 RBI
*Ranked among team leaders in SEC action at .297-3-23
*Solid double play tandem with SS Kyle Farmer in helping team set a school record .974 fielding percentage
*Named to NCAA Corvallis Regional All-Tournament team after batting a team-high .529 (9-for-17) with four runs scored, one home run and perfect fielding percentage in 19 total chances
*Led off NCAA Corvallis Regional elimination game against Arkansas-Little Rock with a home run
*Batted .429 (6-for-14) with six RBI in series win at Ole Miss in April
*Clutch performance in 7-6 road win over Kentucky that clinched spot in SEC Tournament, went 3-for-5 with two home runs, two walks and 4 RBI on May 15
*Went 5-for-6 with a double and two RBI against #16 Baylor on Feb. 27
*Had a 12-game hitting streak during the season
2010 (Sophomore): Played in 41 games with 39 starts (32-2B, 7-SS)
*Batted .333 with four home runs and 32 RBI and posted a .964 fielding percentage overall including .975 at second base (only four errors in 161 total chances) and .914 at shortstop (three errors in 35 total chances)
*Missed first part of season due to back injury and offense came alive at the start of SEC play in mid-March including batting .333 in the Auburn series and .467 versus Miss. State
*Went 3-for-5 with three doubles and two RBI against Miss. State on March 28
*Went 3-for-4 including a home run and a career-high four RBI in 12-6 win at #4 LSU
*Registered seven three-hit games during the year
*Batted .310-2-22 in SEC action
*Recipient of the Leon Farmer Baseball Scholarship endowment
2009 (Freshman):
*Played in 61 games with 56 starts (15-2B, 46-SS), batting .263 with five home runs and 24 RBI
*Went 2-for-5 in games against #17 Florida on May 1 and May 3
*Had two hits in games at #11 Ole Miss on April 24 and 25; hit .417 for the series
*Went 2-for-4 with a home run vs. #10 Georgia Tech on April 14
*Went 3-for-4 with two runs and two RBI vs. #25 Mississippi State on March 22. His two-run homer in the fourth gave UGA a 2-1 lead; finished the series 4-for-10
*Drove in four runs at Georgia State on March 18
*Hit .444 (4-for-9) in the Alabama series March 14-15 including a three-run home run in game one; went 2-for-3 with two runs scored and two stolen bases in game three
*Led the team with two hits and scored two runs vs. Le Moyne on March 10
*Hit .333 (4-for-12) in the Arizona series
*Hit safely in first seven games of the season
*Was one of five freshmen who started on opening day
High School: A graduate of Colonial Forge where he played for Shawn Szakelyhidi
*Earned three varsity baseball letters and two basketball letters
*Hit .406 with eight home runs and 26 RBI in leading the Eagles to the region championship and a state runner-up finish
*Named Commonwealth District Co-Player of the Year, All-Area Free Lance-Star Player of the Year, First Team All-Commonwealth District Shortstop, First Team All Northwest Region shortstop, Second Team Group AAA All-State shortstop and Second Team Washington Post All-Metro in 2008
*Spent three years of high school in Oceanside, Calif., at Santa Fe Christian where he played for former Major Leaguer Rick Aguilera
*Named 2007 CIF Player of the Year after leading Santa Fe Christian to a 26-6 mark, batting .438 with 46 RBI
*Hit .494 with five home runs, 21 RBI and 15 stolen bases as a sophomore
Personal: Born Oct. 6, 1989
*Son of Mike and Anne Hyams
*Major: Exercise Science