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Belambra Clubs - Les Ayguades
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- Swimming pool
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TripAdvisor Reviews Belambra Clubs - Les Ayguades Gruissan
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Oh dear....
Friday 26 September
Drove to the village of Homps to visit the brocante (antique and vintage shop) where I selected some items and it was only as I came to pay did I realize that my purse was not in my bag. We returned to the canal boat but no one had handed in a purse. It must be at the house I thought. So home we went. But it wasn't there. We went to the restaurant ...
Bikes and boats
... road which was a bit unnerving as there are large trucks, tractors and cars that, to me, all seem to be on the wrong side of the road. We turned down a less busy road that led through a vineyard which was very pretty with row after row of vines. All the vines were laden with plump, sweet, juicy red grapes. We know this because we 'stole' two to taste them. The skins are tough ...
Just a little too close to the edge in my view
Wednesday 24
Headed south for a coastal drive around the outskirts of
Narbonne to Port-la-Nouvelle. A pretty
town with a lighthouse.
Stopped at Port-Vendres.
A harbor full of sailing boats and lots of restaurants where we found a restaurant serving moules and frites (mussels and fries).
In search of a lighthouse to view, we drove a very narrow scary
road around the cliff.
Castle day
Tuesday 23 September
Today was Cathar castles day. First stop was at Lagrasse which is a pretty
village with lots of coloured shutters and narrow alleyways. While the others went to view the castle I
went to the Brocante where I found lots of great things. We then moved onto Villerouge-Termenes. The castle is fairly well intact and we
enjoyed lunch viewing the castle walls.
A long drive along ...
We made it to the Med
... OMG it was FREEZING - my legs started to ache like an icecream headache - unbelievable, a wave came and the wind blew the top of the wave onto us and ok time to get in. Shock horror - well it certainly cooled the body temperature down. We sat and took in the scene on our tiny piece of sand surrounded by all the holiday makers, looked at each other and said - yep lets go - coast to coast complete!! Too crowded for us. We went to find lunch ...


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A collection of our articles relating to the NFL Labor battle
Patriots QB accepts $1 million base in 2013 to help team with cap space.
Dolphins running back suffered knee injury.
NOV 26 Joel Corry
Inside a performance-based contract
Elvis Dumervil will be handsomely rewarded after his big night in New Orleans.
NOV 25 Jeff Fedotin
Does Mike Evans deserve Rookie of the Year?
Tampa Bay wide receiver has a TD in four straight games.
NOV 20 Joel Corry
Will there be first ballot Hall of Famers in 2015?
A detailed look at the eight candidates vying for that unique honor.

subset: commoncrawl


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Waste recycled for the catwalk
A sustainable fashion designer to the Oscars' crowd has urged designers to take a more environment friendly approach to making clothes.
A sustainable fashion designer to the Oscars' crowd has urged designers to take a more environment friendly approach to making clothes.
It is early days but in time the Planning Court should evolve into a concept we are familiar with and which will then inevitably have more substantial impact.
Judith Damerell is head of planning at Lewis Silkin LLP
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How can England's stagnant recycling rate be boosted? Phillip Ward suggests strong data along with good communications can play a vital role in nudging the rate up to more reassuring levels
The NHS spent £86m last year disposing of clinical waste, but proper management of healthcare waste is a must, not just for healthcare professionals, but also for tattooists and salons, writes Matthew Smith
An application to vary conditions to allow waste to be stored outside an industrial unit used as a materials recycling facility has been allowed by East Sussex County Council.
East Sussex County Council has approved an application for a new building at a waste management facility near Hailsham.
Lancashire County Council has refused to permit the construction of a bund because of its location in the countryside and in an area where there was a high likelihood of flooding.
A recycling, recovery and processing facility for construction and demolition waste on a 9.4-hectare site in Stanwell Moor, near Heathrow Airport, has been approved by Surrey County Council subject to referral to the secretary of state as a departure...
When acquiring a site, the risk of floods must be considered. If there is a potential risk (for example, it is near a river), your lawyers will typically obtain a desk-top report about flood risk on your behalf.
The correct management of waste is of prime importance to the environment and the UK economy.
There was much positivity and enthusiasm, albeit tinged with a dose of reality, at this year's RWM show, held with the Chartered Institution of Wastes Management (CIWM) at Birmingham's NEC.
In July, Zero Waste Scotland launched a "carrier bag commitment" for retailers, ready for the introduction of single-use carrier bag charging in October. The carrier bag commitment will recognise businesses that donate the proceeds of the 5p bag char...


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Scrap Metal Dealers Aberdare
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Ramsdens Pawnbrokers Aberdare6 Commercial StreetCF44 7RW Aberdare01685 874920
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Cash Generator Aberdare11 Canon StreetCF44 7AT Aberdare01685 878010Closed
The first Cash Generator store was opened in 1994 in Bolton and now it has more than 150 stores throughout the UK. Customers have the possibility to access tens of thousands of bargains including new...
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Typically we trade Monday to Saturday 9:00am to 5:30pm. Do you need cash right away The Cash Generator is here to offer you the best deals possible at an affordable price. The company is buying and...
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The core business of Mayphil has remained the automotive reciprocating engine. The Company grew and quickly established long-lasting relationships in the automotive engineering sector with several...
Glamorgan Ventures LimitedMin Y Coed Darren Ddu Road, YnysybwlCF37 3HE Ynysybwl
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I stayed here for three nights on business. Very helpful hotel staff. The room was very large and not what I'm accustomed to traveling in Europe. The downside was the TV was very small. Internet worked very well. The power outlets were not very convenient but I managed. The train station was across the street. Very convenient to get back... More
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Stacey Rhoades • 2 years ago
Fall landscape with first step of learning perspective. Art Projects for Kids
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Browsing the "Jordan Fly Wade 2" Tag
JORDAN FLY WADE 2 The Jordan Fly Wade 2 is Dwyane Wade's second signature model with Jordan Brand. The sneaker was worn by Wade as he played for the Miami Heat during the shortened 2011-12 season, one that ended in an eventual Championship for the Heat. The Jordan Fly Wade 2 also comes in the post season version worn by Wade in the playoffs known as the Jordan Fly Wade 2 EV.
NBA Feet: Around The League – 4/12 – 4/13
April 13, 2012 BY John Kim / 0 0 / 5
Finishing off another solid week of NBA Feet is a recap of Wednesday and Thursday games, which featured plenty of Air Jordans, Player Exclusives, and Nike Retro Basketball kicks. Gilbe...Read More
Jordan Fly Wade Flight PO
March 13, 2012 BY John Kim / 15 0 / 5
The introduction of Flywire technology to Jordan Brand performance models was certainly an 'advancement' of sorts – just take note of the Jordan Melo M7 Advance that ...Read More
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With the Jordan Brand 'College Collection' dropping tomorrow, how about we take a look back at Melo, Wade, and CP3′s greatest college-time achievements? Dwyane Wade l...Read More
Jordan Fly Wade 2 – Black – White | Release Reminder
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March 1, 2012 BY John Kim / 0 0 / 5
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Home :: Ladies Diamond Rings :: Diamond Engagement Rings :: Diamond Engagement Ring
14K White Gold
1.00 ct.
Product Selection
I was searching for rings all over the web and i came across Joshua Jewelry, after browsing the website, i fell in love with one of the sets, the fact...
Dear Jonathan,
I received my ring on April 9 2009 and I would like to thank you for all your help, the minute that I placed my order online, it was...
Wedding Band
The wedding band I ordered is beautiful. I love it! My future husband is so excited to wear the ring. The quality is excellent! I was very impressed with...
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No Throat-Slitting! Part 2
kaleygeminni on Nov. 14, 2014
Ino Man at 5:39PM, Nov. 18, 2014
That takes me back.
Dipti at 6:53PM, Nov. 16, 2014
woohoo scissors to the throat for the win!!!
Kou the Mad at 2:54PM, Nov. 16, 2014
them little psychic chillin' gonna mess you up.
man in black at 6:49PM, Nov. 14, 2014
Should of acted faster
picosux224 at 6:39PM, Nov. 14, 2014
nastalga i remember this scene. Yun can be scary when she wants to be...
tupapayon at 4:18AM, Nov. 14, 2014
Ah! Busted... those little ones can be sneaky... it's like they could read his mind...
Darius Drake at 1:01AM, Nov. 14, 2014
She should move that pair of scissors. Threatening his hair may scare him more.


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Braden River needs your vote
Date: August 25, 2010
by: The Observer Staff
Braden River Middle School needs the community's help implementing a step dance program.
The school has applied for a $5,000 grant through the Pepsi Refresh Everything Project. Voting takes place online at www.refresheverything.com through Aug. 31.
Voters also can cast ballots by text-messaging the number 101147 to 73774. Standard text-messaging fees apply.
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- Dec
3 Advent Study
7:00 pm - 8:30 pm
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6 17th Annual Jingle & Jog Road Race and 1 Mile Fun Walk
8:00 am
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6 Manatee Aubuon - OPEN HOUSE at Felts Audubon Preserve
8:00 am - 11:00 am
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7 6th Annual Charity Event
12:00 pm - 4:00 pm
Mall announces holiday hours
The Mall at UTC will open early for Black Friday.
Cops Corner: East County
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Weather: East County
Visit YourObserver.com to submit your local weather photos. Each weekly winner will be entered into a monthly drawing for a $25 gift card. One grand prize winner will receive a $5,000 flooring makeover.*


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How to Build a Home Gym Anywhere
Get the right gear to workout in the backyard, the garage, or even in your office.
Dynamax Medicine Ball
This versatile training tool adds intensity to classic moves like medicine-ball pushups, and moves like rotational lunges target multiple muscle groups. The 20-lb "burly" will be a challenging starting point.
Fitness on the Fly: 3-Move Med Ball Core Workout >>>
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Winter Kisses
By A.C. Arthur
(Harlequin Kimani, Mass Market Paperback, 9780373862375, 224pp.)
Publication Date: November 2011
Shop Local
Enter your zip code below to find indies closest to you.
After "the love of her life" broke her heart, Monica Lakefield vowed never to trust a sexy, sweet-talking man again. Dubbed the Ice Queen, she hides her hurt beneath her cool, corporate facade. Until the workaholic Lakefield heiress arrives at an exclusive Aspen resort and discovers hunky Alexander Bennett in her room!
As CFO of his own company, Alexander works hard and plays harder. After being tricked into a vacation by his matchmaking relatives, he finds himself snowbound with the reserved yet sinfully sexy Monica. In front of a roaring fire, with the snow falling outside, he'll show the all-business businesswoman what real passion can be. He'll take nothing less than her kisses. Her heart. And all the love she has to give
Artist C. Arthur was born and raised in Baltimore, Maryland where she currently resides with her husband and three children. Determined to bring a new edge to romance, she continues to develop intriguing plots, sensual love scenes, racy characters and fresh dialogue—thus keeping the readers on their toes! Artist loves to hear from her readers and can be reached through her contact form or via email at email@example.com
"It's refreshing to finally meet two characters who appreciate the necessity of a proper courtship" "Readers...will root for a heroine who is anything but stereotypical" --RT Book Reviews on SING YOUR PLEASURE


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Good view, heavy lateral winds, no gas for long distances, some check points but all good and interesting.
This was a nice drive and I saw Guanaco,Rhea, Fox, Flamingo, Condor, Hawks and many other birds. Not many cars on when I went.
The newly done parts are a dream, cement roads that are like driving on a baby's bum… The still to be completed portions of ruta 9 however are more like a heavy rash!!! Hope this review was helpful!
We drove part of Ruta 9 on the way North from Punta Arenas to Otway Sound. The road was paved and except for semi trucks traffic was at a minimum so the going was good until turning onto the long, long gravel road to Otway!
After exiting the city we passed through some rather monotonous flat areas of farmland and...
Part of this route was not smooth at all and the ride was quite bumpy. The part which was good was great to drive on.
Rent bikes from an outfitter in town (they likely wont be of high quality) and ask to borrow a patch kit and some spare tubes. Then head south as far as you like. Traffic drops off quickly on the edge of town and you'll have gorgeous views of the strait and old farmhouses. Stop for lunch on the side of...
From Punta Arenas to Cerro Castillo the paved route is excellent although there are some minus interruptions (from Punta Arenas to the airport). There will be two ways soon, that's why. Although there are no gas stations between main cities you can find one near the crossroad to Monte Aymond (crossing border).
We enjoyed our trip down Ruta (Route) 9 from Punta Arenas to Fort (Fuerte) Bulnes. It is paved about 2/3 of the way, then becomes well-packed gravel to the fort. It is a dramatic drive, running along the shore of the Strait of Magellan with Tierra del Fuego in the distance. There are ports with fishing boats, fishing boats beached,...
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BEIRUT: More than 20 employees were laid off earlier this week at the Beirut-based Arabic daily Al-Akhbar newspaper, sources at the paper told The Daily Star Friday.
The sources did not specify the reason for the layoffs, but financial and political troubles were not ruled out.
However, sources close to the paper said that the moves were part of a restructuring that includes the launch of Al-Akhbar's English website to complement its popular Arabic online paper.
Al-Akhbar's daily circulation is estimated to be between 8,000 and 16,000 copies.
The paper was launched on Aug. 14, 2006, at the conclusion of the Lebanon-Israel war and was established by veteran journalist Joseph Samaha.
On May 5, Al-Joumhouria newspaper released details from a WikiLeaks cable dated Nov. 12, 2006, concerning a meeting between then U.S. Ambassador to Lebanon Jeffrey Feltman and current Prime Minister-designate Najib Mikati, in which Mikati said he had provided Al-Akhbar with seed money of $150,000. During the meeting Mikati also expressed regrets about funding the paper, according to the cable.
"I'm ashamed of having had provided the newspaper with $150,000 as a preliminary budget," Mikati is said to have told Feltman.
The cable said that Mikati refused "to get involved anymore" with Al-Akhbar because of its "blatant propaganda campaigns," adding that he isn't one of the newspaper owners.
Al-Akhbar, described last year as daring by the New York Times, was among the first papers to publish Lebanon-related WikiLeaks cables. It has been repeatedly criticized for its pro-March 8 editorial line and its support for Hezbollah.
The secretary general of Hezbollah, Sayyed Hassan Nasrallah, commented last month that Al-Akhbar was "not run by [Hezbollah], and not committed to [the party's] policy or ideology."
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Spotlight Recipe: Strawberry Watermelon Slushby Katie Cavuto-Boyle in Healthy Recipes, June 23, 2009
You can't go wrong with cool, sweet drinks on those dog days. Last week, I shared two classics: Berry Spritzer and Refrigerator Tea. Here's another favorite to toast summer's arrival. Made from two fruits that are coming into season, this "slush" is perfect for a party (you'll want to up the portions) or an afternoon snack with the family.
Strawberry Watermelon Slush
2 servings
1 cup frozen or fresh strawberries (if frozen, look for ones with no added sugar)
1 1/2 cups chopped watermelon, seeds removed
1/4 cup seltzer
1 lemon, juiced
1/2 tablespoon agave nectar or honey
4-6 mint leaves
1 cup ice
Combine all ingredients in a blender, mix and serve.
Nutrition Info:
Calories: 80
Total Fat: 0 grams
Saturated fat: 0 grams
Cholesterol: 0 milligrams
Sodium: 0 milligrams
Total Carbohydrates: 20 grams
Total Fiber: 2 grams
Sugars: 15 grams
Protein: 1 gram
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Comments (4 )
I just made this as it's hit the 90s here in South Florida… it's delicious and very refreshing! I must admit though, I added a tablespoon of sugar in addition to the agave… I also might try lime in place of the lemon next time. Thanks, Katie!
Glad you enjoyed it! My favorite thing about a recipe like this is there is room for interpretation! The lime sounds delish!!
Sounds good. Can you substitute the seltzer with tonic water or club soda? I can't stand seltzer water.
Of course…you can use sparkling water, tonic or club…even some champagne…anything with a little fiz though depending on your choice it might change the nutrition information a bit! Seltzer is calorie and sodium free while club soda has sodium and tonic has sodium and is caloric…FYI


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HyperBIT Entertainment is a studio founded for the purpose of developing games built by those with a real passion for development.
Our first project 'Project Beast' is in the conceptual stages at the moment! Watch this space.
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A Wall Street Journal article debunked the myth that federal disability benefits are to blame for the shrinking labor force, "exaggerated" claims that have previously been pushed by the paper itself.
An April 29 Journal article headlined "Real Culprit Behind Smaller Workforce: Age" explained that the recent decrease in the labor force -- the number of employed and unemployed Americans who are currently seeking work -- "has more to do with retiring baby boomers than frustrated job seekers abandoning their searches." The article noted that claims that Americans are voluntarily leaving the workforce to receive Disability Insurance instead of working, for example, "may be exaggerated," and explained that retirees and students made up a far more significant portion of those leaving the labor force. The article included the following graph, showing disability was the least common reason for individuals leaving the workforce in March 2013:
However, the Journal has previously pushed the myth that Disability Insurance accounted for much of the dropping labor force participation rate. An April 10 article headlined "Workers Stuck in Disability Stunt Economic Recovery" claimed that workers receiving disability benefits were costing the economy billions by not instead participating in the labor force, and quoted economist Michael Feroli's claim that "worker flight to the Social Security Disability Insurance program accounts for as much as a quarter of the puzzling drop in participation rates, a labor exodus with far-reaching economic consequences." These claims are in direct contradiction to the Journal's most recent reporting.
According to Center for Economic and Policy Research co-director Dean Baker, research shows if more individuals who receive disability benefits worked, it would have a relatively minor effect on employment figures. Harold Pollack, an expert on disability policy at the University of Chicago's School of Social Service Administration, dismissed the idea that disability benefits might be "luring away people who could work." Despite these facts, media continue to attack federal disability benefits by pushing the false claim that disability programs harm the economy.
Fox News forwarded the notion that it might be appropriate for school children to be forced to work in exchange for free school meals, after a Republican lawmaker in West Virginia proposed such a requirement for a new law curbing child hunger.
On Fox & Friends First, on-screen text asked viewers whether students should have to "work for their school meals":
As The Washington Post blog "She The People" explained, the idea that students could be forced into labor in exchange for food comes from a Republican member of the West Virginia House of Delegates, who suggested the requirement be added to a bill intended to ensure no child goes hungry:
"I think it would be a good idea if perhaps we had the kids work for their lunches: trash to be taken out, hallways to be swept, lawns to be mowed, make them earn it," said Ray Canterbury, a Republican from Greenbrier and a member of the West Virginia House of Delegates, during debate over Senate Bill 663, also known as the Feed to Achieve Act.
The bill -- the first of its kind in the nation -- would create a partnership between private donations and public funds to make breakfast and lunch available for free to every student, kindergarten through high school senior, in West Virginia. It's based on a model program in Mason County that's improved attendance and decreased discipline problems, according to the school district's food service director.
Free meals are provided through the National School Lunch Program to students whose family's income is 130 percent or less of the federal poverty guidelines. For this past school year, that means a family of four with an annual income of $29,965 qualifies. Children with household incomes of 185 percent or less of the poverty guidelines can get reduced-price meals under the program, which -- I was surprised to learn -- was established in 1946 by the National School Lunch Act.
West Virginia's Feed to Achieve Act wants to go beyond that by making sure no child goes hungry at school, but Canterbury repeated the theme of "there is no such thing as a free lunch" during the delegates' discussion of the bill, which had passed the state Senate unanimously.
Media outlets including NPR and Fox News are targeting federal disability benefits programs through a campaign deceptively portraying these programs as wasteful and unsustainable. In reality, these programs have low fraud rates and help the rising number of Americans with severe disabilities survive when they are unable to work.
Washington Examiner senior political columnist Tim Carney is using the murder trial of Dr. Kermit Gosnell to demonize an exceptionally rare type of legal abortion that is used to save the life of a mother.
Gosnell has been charged with eight counts of murder, horrific acts committed under the guise of women's health services that are detailed by a grand jury report and which an expert on reproductive health explained are not in line with legal abortion procedures.
In an April 16 Examiner column, Carney fixated on remarks made by Dr. Tracy Weitz, a reproductive health professor at the University of California, during a conference call with pro-choice group RH Reality Check. Carney highlighted her descriptions of a particular abortion procedure to imply that the only difference between Gosnell's methods and legal abortions was whether or not the procedure was performed "when the fetus is still in the uterus, not when the fetus has been delivered."
But as Dr. Weitz explained in her response to Carney, the procedures Gosnell is alleged to have done have "nothing to do with the way in which the standard of care and later abortion procedures are performed in the United States" and his actions are "nowhere in the medical literature." Similarly, Salon's Irin Carmon explained that "[n]o one who supports the provision of safe abortion care to women excuses any of what Gosnell is accused of, from willfully gruesome conditions to sadistic treatment to infanticide."
Carney's bogus analogy of legal abortion procedures to the Gosnell case further ignores the fact that legal "late-term" abortions -- which is not a medical term -- are extremely rare, making up only about 1 percent of all abortions in the United States, and are significantly restricted by law. According to research by the Guttmacher Institute, the vast majority of states prohibit abortions after fetus "viability," which occurs at approximately 20 to 24 weeks, prior to the third trimester. Some states provide an exception, allowing a medical professional to perform a late-term abortion when the life of the mother is threatened, and in even fewer states, cases of "fetal abnormality."
Furthermore, contrary to Gosnell's alleged actions, legal abortion is very safe. As Carmon reported, a medical study published in 2012 concluded that "[l]egal induced abortion is markedly safer than childbirth. The risk of death associated with childbirth is approximately 14 times higher than that with abortion."
But these life-saving procedures are under threat as right-wing media figures such as Carney continue to demonize legal, affordable, safe, and rare abortions by implying that they are similar to Gosnell's horrors. As Salon's Carmon further noted, many women went to Gosnell "because they felt they had no alternative." The case is an indictment of the anti-choice movement, revealing the need for safe, affordable, and legal abortion services that protect the health of women.
Right-wing media are encouraging Republican senators to filibuster gun violence prevention legislation, continuing a long history of trying to influence GOP politics through recommended obstructionism.
Fox News figures claimed the U.S. should emulate the United Kingdom by slashing funding to federal disability programs and changing eligibility requirements, despite the fact that U.S. eligibility requirements are already stringent, that the new U.K. benefits tests were largely overturned on appeal, and that research shows changes to disability programs in the U.K. will force thousands of individuals with disabilities into poverty.
Under fire for a sloppy report that leaned on anecdotal evidence to make sweeping generalizations about federal disability benefits, NPR has edited portions of that report even as Ira Glass publicly defends the initial reporting.
On March 22, Media Matters highlighted several myths and errors in a report from NPR's Planet Money about Supplemental Security Insurance, a federal disability program for children. The report drew further criticism, and more than 100 organizations that advocate for and support people with disabilities have signed a letter criticizing the piece, saying it "paints a misleading and inaccurate picture of the Social Security programs that serve as a vital lifeline for millions of Americans with severe disabilities."
On March 26, This American Life host Ira Glass responded to Media Matters' criticism by claiming he stood by his program's work, saying "our report on disability programs was fact checked line by line by an outside fact checker, in addition to fact checking by the reporter and her editors" and that "We know of no factual errors. We stand by the story."
But while Glass publicly claimed to stand behind the story, Wired Business senior writer Ryan Tate has noted that the online text version of the radio program has been altered since its original posting.
NPR has since said that the changes were made "for clarity after publication."
Right-wing media are claiming that the federal government spent money on research grants and other expenses for puppets during the automatic budget cuts known as sequestration, despite the fact that the grants were all paid prior to the budget cuts.
On Wednesday, Breitbart.com attacked the administration for stopping tours of the White House as a result of budget cuts in a post titled "U.S. Spends $1.18 Million On Puppets Amid Sequester," and claimed the government could "cut federal 'puppet expenditures' to keep the people's house open." The website listed spending from the National Science Foundation and the National Endowment for the Arts, among other sources, as federal spending on "puppets and puppetry-related expenses."
Fox Nation hyped the Breitbart.com post, labeling it a "report":
Fox & Friends joined in on Thursday when co-host Steve Doocy said: "1.18 million, that's how much the government has spent on puppets since 2009. That's enough to pay for more than a year's worth of White House tours."
However, the grants and contracts that Breitbart.com cited were all paid prior to 2013. A screenshot of the search terms used by Breitbart.com reveals the most recent grants were paid in fiscal year 2012, which ended on September 30, 2012. Sequestration took place on March 1, 2013, almost six months later.
Despite the claims of Fox News and Breitbart.com, these expenditures have nothing to do with the cancelation of White House tours. The spending cited by Breitbart.com did not come out of the budget of the Secret Service, which made the decision to stop providing security for the tours due to its own budget cuts under the sequester.
A misleading NPR report has become fodder for a right-wing media campaign to scapegoat federal disability benefits, despite the fact that the rise in disability claims can be attributed to the economic recession and demographic shifts, and that instances of fraud are minimal.
NPR reported that the rise in the number of federal disability beneficiaries was "startling" and claimed it was explained by unemployed workers with "squishy" claims of disability choosing to receive federal benefits rather than work. Right-wing media called the report "brilliant," and used it to further the myth that the increase in the number of individuals receiving disability benefits reveals fraud in the system.
Breitbart.com's Wynton Hall wrote that NPR's "eye-opening" piece uncovered a disability program "fraught with fraud." Fox Nation promoted the piece with the headline, "Every Month, 14 Million People Get a Disability Check from the Government..." The National Review Online's blog called the piece "brilliant," while the Washington Examiner's editorial offered it as evidence that disability benefits provide "a voluntary life sentence to idle poverty." The Drudge Report linked to the NPR story and to the Breitbart.com article:
But as Media Matters previously noted, these reports failed to include crucial facts that explain the rise in disability benefits. The recent financial crisis and the rising rate of child poverty have made more children eligible to receive benefits through the Supplemental Security program, while the growth in the number of adults receiving benefits through Social Security Disability Insurance since the 1970s is largely explained by increases in the number of women qualifying for benefits. As the Center on Budget and Policy Priorities explained, as women have joined the workforce in greater numbers over the past few decades, more women are eligible for disability benefits, resulting in higher numbers of beneficiaries.
Furthermore, in a report published in March 2012, the Government Accountability Office found that improper payments of disability benefits are not a widespread problem, and accounted for less than four percent of total improper payments made by federal agencies in fiscal year 2011.
Public radio program This American Life pushed a series of myths about Supplemental Security Insurance (SSI), a Social Security program that supports families that include children with disabilities. The piece ignored that the recent rise in disability benefits is tied to the recession and higher rates of poverty, that qualifying for benefits is difficult, that SSI encourages employment, and that the current program has significantly reduced poverty among children with disabilities.


text:
Local News
4th Annual Pigskin Classic – RESULTS (11/20/2014) - RESULTS PIGSKIN CLASSIC RESULTS POOL AND CHAMPIONSHIP BRACKET SCHEDULES PLEASE NOTE : The championship games for 9U and 10U games were played under time constraints (Running Clock) and not under normal game conditions. We would like to apologize to all teams that were involved in these games. Games will not
Sunday Super Showcase Recap 11U- #4 Welcome All Panthers vs #10 Atlanta Cowboys (11/10/2014) - ATLANTA-- After watching the 12u Rock Chapel Bulldogs get upset, the Welcome All Panthers came out full of energy. The emotion was in the air and the best was saved for last to end a great season of football. #1 Kobe Harris moved the chains and drew first blood with
Gresham Park Rattlers make a huge statement @ Sunday Super Showcase (11/10/2014) - ATLANTA– It is getting close to the Pig Skin Classic and if a statement was made last Sunday it was made by the stinging Gresham Park Rattlers. The 11u Rattlers feel that they are not getting the respect in the polls, and put their energy towards the GSA Gladiators. It
Warner Robins Raiders Upsets ( 8) Rock Chapel Bulldogs vs (11/9/2014) - ATLANTA– After the little kids finished playing it was time for some big boy football. The Raiders started the party early with a big time 56 yard run from Jahlen Rutherford. The Bulldogs used their air attack from quarterback Robin Jones and wide out Michael Thompson playing pitch and catch,
Sunday Night Football 6u/8u Recaps – Atlanta Cowboys, Decatur Army pull off win! (11/9/2014) - ATLANTA– Beautiful day in Atlanta, makes a even better day of football -D1Spects Style-. Powers collided early in the 6u Decatur Army vs Ben Hill Tigers. The Army used the legs of Jeremiah Francis and took a commanding 12-0 lead but Kaleb McMicheal would find the end-zone and again score
Free NFL Heads Up Coachin Clinic (11/6/2014) - For more information click here
Anthony Davis Jr. #7 Decatur Army Camo (11/6/2014) - Decatur Army Camo is a 6U team that is blessed talent and size. With a line anchored by #50 Tamiel "Young Clowney" Green , #7 Anthony Davis Jr. has the freedom to run all day. A big back for 6U , Davis showed the
Georgia's Top Ten Youth Football Leagues (11/3/2014) - Atlanta, GA: Being that the South is considered a "Hotbed" for youth and high school football, we at D1 Spects wanted to take the time out and rank the top ten leagues in our state. We base these findings on quality of League information , league play and schedules ,
National Recruiting News
- King beginning to take a look (11/25/2014) - By Brian Snow Five-star V.J. King has new surroundings as a junior, and he is beginning to take a look at his recruiting. …read more Source:: Basketball Today
- Atson helps himself with big weekend (11/25/2014) - By Evan Daniels NEW HAVEN, Conn. — With a host of college coaches looking on, Travis Atson, a 2016 guard, strung together a pair of strong performances at the National Prep Showcase. …read more Source:: Basketball Today
- Doral Moore: Evaluation (11/24/2014) - By Rob Harrington Center Doral Moore still has not achieved anything close to resembling his full potential, but he's a tantalizing prospect who could blossom during the course of his college career. …read more Source:: Basketball Today
- Tyler Dorsey: Evaluation (11/24/2014) - By Rob Harrington Very few players in the 2015 class attracted as much attention early as shooting guard Tyler Dorsey. The native California burst onto the scene even prior to high school, and he began to receive coverage here at Scout during the fall of his freshman season. …read more
- News and Notes: Indiana receiving votes (11/24/2014) - By Justin Albers Indiana received votes in both the AP and USA Today polls for the first time today. Plus, notes on James Blackmon Jr. and Robert Johnson, and Indiana's game vs. Eastern Washington tonight. …read more Source:: Basketball Today
- National Prep Showcase: Day Three (11/24/2014) - By Evan Daniels NEW HAVEN, Conn. — Justin Simon and Donovan Mitchell put together a strong effort for Brewster, while Travis Atson, Matt Turner and Eddie Ekiyor had breakout performances on the third day of the National Prep Showcase. …read more Source:: Basketball Today
- National Prep Showcase: Day Three (11/24/2014) - By Evan Daniels NEW HAVEN, Conn. — Justin Simon and Donovan Mitchell put together a strong effort for Brewster, while Travis Atson, Matt Turner and Eddie Ekiyor had breakout performances on the third day of the National Prep Showcase. …read more Source:: Basketball Today
- Narain off to strong start (11/24/2014) - By Brian Snow Four-star power forward Nolan Narain is off to a strong start this season. …read more Source:: Basketball Today


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K & N Air Filter kit, fits 2005 Dodge 2500 5.7 HEMI - $150
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Nike SB Dunk High "De La Soul" by John Kim 8 Comments
love these. must have in both colorways. keep it up sb.
September 13, 2013 BY Brendan Dunne / 0
The ever busy CNCPTS out of Boston have apparently been hard at work on yet another Christmas-time Nike SB release. Pictured is the Nike SB Dunk High "Ugly Christmas Sweater", a pair that pays tribute to those grotesque garments you're either used to un-wrapping on that day or spotting your relatives in. For what it's worth these are reportedly a scrapped sample, as some of the imagery was apparently to close to some copyrighted material for Nike's comfort-so the final version is apparently significantly different. See the Concepts x Nike SB Dunk High "Ugly Christmas Sweater" below and then tell us in the comments if you approve.
via N-SB Forums
Filed under: Collaboration Dunk Nike SB Upcoming Sneakers
Tags: CNCPTS Nike SB Dunk High
love these. must have in both colorways. keep it up sb.
These are excellent- would love these for the holiday party season.
They definitely are ugly just like their title
these are nice, love the twisted christmas floral look...exactly like nike sb USED to do.
no heat has come from SB dunks this year. retro doesnt count. theres a million ideas they can put into dunks by are making extremely plain joints.
lmao i would soooo wear these while drinking eggnog. ugly but funny & clever
These need to stay a concept, no need for these to release from the vibe Iam getting from the pics so far.
Nike SB Dunk High "De La Soul" by John Kim 8 Comments
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Book Review
The Thought of Work, by John Budd. Cornell University Press, Ithaca, NY, 2011, 264 pp., ISBN 978 0 8014 7761 4, US$24.95, paperback.
Article first published online: 25 FEB 2013
DOI: 10.1111/bjir.12013_3
© Blackwell Publishing Ltd/London School of Economics 2013
British Journal of Industrial Relations
Volume 51, Issue 1, pages 202–203, March 2013
Additional Information
How to Cite
Strangleman, T. (2013), The Thought of Work, by John Budd. Cornell University Press, Ithaca, NY, 2011, 264 pp., ISBN 978 0 8014 7761 4, US$24.95, paperback. British Journal of Industrial Relations, 51: 202–203. doi: 10.1111/bjir.12013_3
Publication History
- Issue published online: 25 FEB 2013
- Article first published online: 25 FEB 2013
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Metal Gear Scanlon 2 - Part 08
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Nintendo's all-stars assemble once again, resulting in one of the best reasons to own a Wii U (and eight GameCube controllers).
The move to more powerful consoles has resulted in a prettier looking wrestling game, but also a far less enjoyable one.
Far Cry 4's open-world provides ludicrous moments and enough chaotic fun to make it worth your while.
Location »
Environments cycle between day and night, often with effects on other aspects of the game.
Dwarves are a short, stout race that appear in any number of fantasy games and stories. They are almost always depicted as short with bushy beards similar to vikings. They can also be identified by their love for ale and gold.
Missions during which players are tasked with protecting a non-playable character or object from harm until a certain goal is met.
Cold-blooded aquatic animals that have scales and breathe through gills.
A gaming genre of its own, but also frequently featured as a mini-game in other titles, especially RPGs.
Goblins are irritable, evil and mischievous creatures in folklore. They can range in size from halfling to average human size.
High Elves is a race in the fantasy genre. They are all good-natured, but are often considered rude or prudish by other races. High Elves are highly intelligent, but also wise, making them great magic users of all types.
Many games allow you to buy stuff, these are the dudes who help sell it to you. Typically they also engage in light conversation.
Orcs/Orks/Orques are a fictional race of tough humanlike creatures, often with green or black skin, originally coming from the Saxon word for the Normans during the invasion, meaning demon or foreigner.
Many games feature poison, but sometimes the art of creating poisons is an available trade skill to learn. Rogues generally excel in this profession.
The foil of almost every early RPG lover, these rodents often live in sewers. While most rats are simple targets, games like Ratatouille make them the hero.
The skeleton is the framework of the human body.
Arguably the most fearsome of all the reptiles - it has scales and no legs. Snakes use a variety of tactics to harm players such as poison, hypnosis, and constriction. The most deadly snakes have mastered the way of stealth.
There are lots of things to do underwater, from exploration to combat. Early games tended to treat water as slower moving blue air, but with advances in technology we're seeing an increasing number of options for underwater action.
Wood Elves are a common race in the fantasy genre. Their affinity to nature leads many to the path of druids or rangers.
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Particles of water insoluble biologically active compounds, particularly water-insoluble drugs, with an average size of 100 nm to about 300 nm, are prepared by dissolving the compound in a solution then spraying the solution into compressed gaz, liquid or supercritical fluid in the presence of appropriate surface modifiers.
1. A process of preparing microparticles up to 300 nm in size of water-insoluble or substantially water-insoluble biologically active compounds comprising the steps of:
(1) dissolving a water-insoluble or substantially water-insoluble biologically active compound in a solvent therefor to form a solution; and
(2) spraying the solution prepared in step (1) into a compressed gas, liquid or supercritical fluid in the presence of a surface modifier dispersed or dissolved in an aqueous phase.
2. A process of preparing microparticles up to 300 nm in size of a water-insoluble or substantially water-insoluble biologically active compound comprising the steps of:
(1) dissolving a water-insoluble or substantially water-insoluble biologically active compound in a compressed fluid;
(2) preparing an aqueous phase containing a surface modifier active at the compound-water interface; and
(3) spraying the compressed fluid of step (1) into the aqueous phase of step (2) to form microparticles of the compound.
3. The process according to
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[0001] This invention provides a novel process for producing sub-micron sized particles of water insoluble compounds with biological uses, particularly water insoluble drugs.
[0002] Approximately one-third of the drugs in the United States Pharmacopoeia are water-insoluble or poorly water-soluble. Many currently available injectable formulations of such drugs carry important adverse warnings on their labels that originate from detergents and other agents used for their solubilization. Oral formulations of water-insoluble drugs or compounds with biological uses frequently show poor and erratic bioavailability. In addition, water-solubility problems delay or completely block the development of many new drugs and other biologically useful compounds.
[0003] Two alternative approaches for insoluble drug delivery are microparticles which involves forming a phospholipid stabilized aqueous suspension of submicron sized particles of the drug (see U.S. Pat. No. 5,091,187; 5,091,188 and 5,246,707) and microdroplets which involves forming a phospholipid stabilized oil in water emulsion by dissolving the drug in a suitable bio-compatible hydrophobic carrier (see U.S. Pat. No. 4,622,219 and 4,725,442).
[0004] The pharmacokinetic properties of both oral and injectable microparticle formulations are dependent on both the particle size and phospholid surface modifier. However, with certain water insoluble compounds the current employed methods of particle size reduction are problematic. Thus, the overall objective of this invention is to develop a novel process based on the use of compressed fluids, including supercritical fluid technology, that yields surface modifier stabilized suspensions of water insoluble drugs with an average particle size of 100 nm to about 300 nm and a narrow size distribution. The inventive process is robust, scalable and applicable to a wide range of water-insoluble compounds with biological uses.
[0005] The invention is further explained with reference to the attached drawings in which
[0006]FIG. 1 is a schematic representation of an apparatus for carrying out the present invention by precipitating the bioactive substance by rapid expansion from a supercritical solution;
[0007]FIG. 2A is a more detailed representation of the preheater assembly of FIG. 1;
[0008]FIG. 2B is an enlarged perspective view of the expansion nozzle of FIG. 1;
[0009]FIG. 3 is a schematic representation of an apparatus for preparing sub-micronsized particles according to the invention by precipitating a bioactive substance, suitably solubilized, into a compressed gas, liquid or supercritical fluid;
[0010]FIG. 4 is a graph showing the particle size distribution on a volume weighted basis of the cyclosporine particles produced in Example 1 expanded into a phospholipid containing 1 wt % stabilizer;
[0011]FIG. 5 is a graph showing the particle size distribution on a volume weighted basis of the cyclosporine particles produced in Example 1 expanded into a phospholipid containing 2 wt % stabilizer;
[0012]FIG. 6 is a graph showing the particle size distribution on a volume weighted basis of the indomethacin particles produced in Example 3 sprayed directly into carbon dioxide;
[0013]FIG. 7 is a graph showing the particle size Gaussian distribution on a volume weighted basis of the indomethacin particles produced in Example 3 sprayed into a phospholipid containing 2 wt % stabilizer;
[0014]FIG. 8 is a graph showing the particle size distribution on a volume weighted basis of the tetracaine hydrochloride particles produced in Example 4 sprayed into carbon dioxide and water;
[0015]FIG. 9 is a graph showing the particle size distribution on a volume weighted basis of the tetracaine hydrochloride particles produced in Example 4 sprayed into carbon dioxide and water also containing 1 wt % of stabilizer; and
[0016]FIG. 10 is a graph showing the particle size Gaussian distribution on a volume weighted basis of tetracaine hydrochloride particles produced in Example 4 sprayed into carbon dioxide, water and 2 wt % stabilizer.
[0017] This invention is a process using compressed fluids to produce submicron sized particles of industrially useful poorly soluble or insoluble compounds with biological uses by: (1) precipitating a compound by rapid expansion from a supercritical solution (Rapid expansion from supercritical solution) in which the compound is dissolved, or (2) precipitating a compound by spraying a solution, in which the compound is soluble, into compressed gas, liquid or supercritical fluid which is miscible with the solution but is antisolvent for the compound. In this manner precipitation with a compressed fluid antisolvent (Compressed fluid antisolvent) is achieved. Optionally, the process combines or integrates a phospholipid in water or other suitable surface modifiers such as surfactants, as may be required, into the processes. The surfactant is chosen to be active at the compound-water interface, but is not chosen to be active at the carbon dioxide-organic solvent or carbon dioxide compound interface when carbon dioxide is used as the supercritical solution. A unique feature of this invention is the combination of either rapid expansion from supercritical solution or compressed fluid antisolvent with recovery of surface modified stable submicron particles in an aqueous phas.
[0018] By industrially useful insoluble or poorly soluble compounds we include biologically useful compounds, imaging agents, pharmaceutically useful compounds and in particular drugs for human and veterinary medicine. Water insoluble compounds are those having a poor solubility in water, that is less than 5 mg/ml at a physiological pH of 6.5 to 7.4, although the water solubility may be less than 1 mg/ml and even less than 0.1 mg/ml.
[0019] Examples of some preferred water-insoluble drugs include immunosuppressive and immunoactive agents, antiviral and antifungal agents, antineoplastic agents, analgesic and anti-inflammatory agents, antibiotics, anti-epileptics, anesthetics, hypnotics, sedatives, antipsychotic agents, neuroleptic agents, antidepressants, anxiolytics, anticonvulsant agents, antagonists, neuron blocking agents, anticholinergic and cholinomimetic agents, antimuscarinic and muscarinic agents, antiadrenergic and antarrhythmics, antihypertensive agents, antineoplastic agents, hormones, and nutrients. A detailed description of these and other suitable drugs may be found in Remington's Pharmaceutical Sciences, 18th edition, 1990, Mack Publishing Co. Philadelphia, Pa.
[0020] Cyclosporine, a water insoluble immunosuppressive drug, is used as a model to illustrate the invention. This drug was chosen since it has not been possible by using conventional size reduction techniques to achieve the particle size and distribution believed necessary to reach the desired pharmacokinetic performance.
[0021] Cyclosporine is a water insoluble, lipophilic 11 amino acid polypeptide with unique immunosuppressive properties. Its major use is as an immunosuppressant in solid organ transplantation. The clinical utility of the currently available pharmaceutical dosage forms are severely limited by the drug's insolubility. That is, the bioavailability of the oral form is low and the intra and inter patient absorption is variable.
[0022] The phospholipid may be any natural or synthetic phospholipid, for example phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, phosphatidylglycerol, phosphatidic acid, lysophospholipids, egg or soybean phospholipid or a combination thereof The phospholipid may be salted or desalted, hydrogenated or partially hydrogenated or natural semisynthetic or synthetic.
[0023] Examples of some suitable second surface modifiers include: (a) natural surfactants such as casein, gelatin, tragacanth, waxes, enteric resins, paraffin, acacia, gelatin, cholesterol esters and triglycerides, (b) nonionic surfactants such as polyoxyethylene fatty alcohol ethers, sorbitan fatty acid esters, polyoxyethylene fatty acid esters, sorbitan esters, glycerol monostearate, polyethylene glycols, cetyl alcohol, cetostearyl alcohol, stearyl alcohol, poloxamers, polaxamines, methylcellulose, hydroxycellulose, hydroxy propylcellulose, hydroxy propylmethylcellulose, noncrystalline cellulose, polyvinyl alcohol, polyvinylpyrrolidone, and synthetic phospholipids, (c) anionic surfactants such as potassium laurate, triethanolamine stearate, sodium lauryl sulfate, alkyl polyoxyethylene sulfates, sodium alginate, dioctyl sodium sulfosuccinate, negatively charged phospholipids (phosphatidyl glycerol, phosphatidyl inosite, phosphatidylserine, phosphatidic acid and their salts), and negatively charged glyceryl esters, sodium carboxymethylcellulose, and calcium carboxymethylcellulose, (d) cationic surfactants such as quaternary ammonium compounds, benzalkonium chloride, cetyltrimethylammonium bromide, chitosans and lauryldimethylbenzylammonium chloride, (e) colloidal clays such as bentonite and veegum. A detailed description of these surfactants may be found in Remington's Pharmaceutical Sciences, and Theory and Practice of Industrial Pharmacy, Lachman et al, 1986.
[0024] More specifically, examples of suitable second surface modifiers include one or combination of the following: polaxomers, such as Pluronic� F68, F 108 F127, which are block copolymers of ethylene oxide and propylene oxide available from BASF, and poloxamines, such as Tetronic� 908 (T908), which is a tetrafunctional block copolymer derived from sequential addition of ethylene oxide and propylene oxide to ethylene-diamine available from BASF, Triton� X-200, which is an alkyl aryl polyether sulfonate, available from Rohm and Haas. Tween 20, 40, 60 and 80, which are polyoxyethylene sorbitan fatty acid esters, available from ICI Speciality Chemicals, Carbowax� 3550 and 934, which are polyethylene glycols available from Union Carbide, hydroxy propylmethylcellulose, dimyristoyl phosphatidylglycerol sodium salt, sodium dodecylsulfate, sodium deoxycholate, and cetyltrimethylammonium bromide.
[0025] Particles produced by the process of this invention are generally at most 500 nm in size usually below 300 nm, desirably less than 200 nm, preferably less than about 100 nm and often in a range of 0.1 to 100 nm in size. These particles are narrowly distributed in that 99% of the particles are below 500 nm and preferably below 400 nm with peaks at half width at half height at about 200 nm and preferably below 100 nm. The particles may be recovered from suspension by any convenient means such as spray drying, lyophilization, diafiltration, dialysis or evaporation.
[0026] The solvent properties of supercritical fluids are strongly affected by their fluid density in the vicinity of the fluid's critical point. In rapid expansion from supercritical solutions, a non volatile solute is dissolved in a supercritical fluid. Nucleation and crystallization are triggered by reducing the solution density through rapid expansion of the supercritical fluid to atmospheric conditions. To achieve this the supercritical fluid is typically sprayed through 10-50 microns (internal diameter) nozzles with aspect ratios (L/D) of 5-100. The fluid approaches sonic terminal velocity at the nozzle tip and high levels of supersaturation result in rapid nucleation rates and limited crystal growth. The combination of a rapidly propagating mechanical perturbation and high supersaturation is a distinguishing feature of rapid expansion from a supercritical solution. These conditions lead to the formation of very small particles with a narrow particle distribution.
[0027] The first comprehensive study of rapid expansion from a supercritical solution was reported by Krukonis (1984) [V. J. Krukonis: AIChE Annual Meeting San Francisco (1984), as cited in J. W. Tom et al.: Supercritical Fluid Engineering Science, Chapter 19, p238, (1993)] who formed micro-particles of an array of organic, inorganic, and biological materials. Most particle sizes reported for organic materials, such as lovastatin, polyhydroxyacids, and mevinolin, were in the 5-100 micron range. Nanoparticles of beta-carotene (300 nm) were formed by expansion of ethane into a viscous gelatin solution in order to inhibit post expansion particle aggregation.
[0028] Most rapid expansion from supercritical solution studies on organic materials utilize supercritical carbon dioxide. However, ethane was preferred to carbon dioxide for beta-carotene because of certain chemical interactions. Carbon dioxide is generally preferred, alone or in combination with a cosolvent. Minute additions of a cosolvent can increase the solubility of some solutes by orders of magnitude. When cosolvents are used in rapid expansion from a supercritical solution, care is required to prevent desolution of the particles due to solvent condensing in the nozzle. Normally, this is achieved by heating, the supercritical fluid, prior to expansion, to a point where no condensate (mist) is visible at the nozzle tip.
[0029] A similar problem occurs when carbon dioxide is used alone. During adiabatic expansion (cooling), carbon dioxide will be in two phases unless sufficient heat is provided at the nozzle to maintain a gaseous state. Most investigators recognize this phenomenon and increase the pre-expansion temperature to prevent condensation and freezing in the nozzle. A significant heat input is required (40-50 kcal/kg) to maintain carbon dioxide in the gaseous state. If this energy is supplied by increasing the pre-expansion temperature the density drops and consequently reduces the supercritical fluid's solvating power. This can lead to premature precipitation and clogging of the nozzle.
[0030] There are a number of advantages in utilizing compressed carbon dioxide in the liquid and supercritical fluid states, as a solvent or anti-solvent for the formation of materials with submicron particle features. Diffusion coefficients of organic solvents in supercritical fluid carbon dioxide are typically 1-2 orders of magnitude higher than in conventional liquid solvents. Furthermore, carbon dioxide is a small linear molecule that diffuses more rapidly in liquids than do other antisolvents. In the antisolvent precipitation process, the accelerated mass transfer in both directions can facilitate very rapid phase separation and hence the production of materials with sub-micron features. It is easy to recycle the supercritical fluid solvent at the end of the process by simply reducing pressure. Since supercritical fluids do not have a surface tension, they can be removed without collapse of structure due to capillary forces. Drying of the product is unusually rapid. No carbon dioxide residue is left in the product, and carbon dioxide has a number of other desirable characteristics, for example it is non-toxic, nonflammable, and inexpensive. Furthermore, solvent waste is greatly reduced since a typical ratio of antisolvent to solvent is 30:1.
[0031] As an antisolvent, carbon dioxide has broad applicability in that it lowers the cohesive energy of nearly all organic solvents. In 1992, D. J. Dixon, PhD. Dissertation, University of Texas at Austin, described a process in which liquid solutions of polymer in solvent are sprayed into compressed carbon dioxide to form microspheres and fibers. In this process, so called precipitation with a compressed fluid antisolvent, the polymer is insoluble in carbon dioxide, and the organic solvent is fully miscible with CO2. This concept has been used to form biologically active insulin particles (4 microns) [Yeo, S. D., Lim, G. B. and Debenedetti, P. G. Formation of Microparticulate Protein Powders using a Supercritical Fluid Anti-Solvent Biotechnol, and Bioeng. 1993, 341], several micron biodegradable L-poly(lactic acid) particles [Randolph, T. W. B., R. A.; Johnston, K. P. Micron Sized Biodegradeable Particles of Poly(L-lactic Acid) via the Gas Antisolvent Spray Precipitation Process. Biotechnology Progress. 1993, 9, 429] and methylprednisolone acetate particles (<5 microns) [W. J. Schmitt, M. C. S., G. G. Shook, S. M. Speaker. Finely-Divided Powders by Carrier Solution Injection into a Near or Supercritical Fluid. Am. Inst. Chem. Eng. J. 1995, 41, 2476-2486]. Somewhat surprisingly, the particle sizes have been as small as those made by rapid expansion from a supercritical solution, despite the potentially faster times for depressurization in rapid expansion from a supercritical solution versus two-way mass transfer in the Compressed fluid antisolvent process. Not only can the compressed fluid antisolvent process produce PS particles, but also solid and hollow fibers highly oriented microfibrils biocontinuous networks and 100 nm microballoons with porous shells.
[0032] To date, it has not been possible to make submicron particles by the compressed fluid antisolvent process without particle aggregation or flocculation. Our objective is to overcome this limitation with the use of surface modifiers, also termed surfactant stabilizers, such as phospholipids, salts of cholic and deoxycholic acids, Tweens (polyoxyethylene sorbitan esters), Pluronic F-68, Tetronic-908, hydroxypropylmethyl cellulose (HPMC), Triton X-100, cetyltrimethylammonium bromide, PEG-400 or combinations of these compounds as described in more detail above.
[0033] Considerable variations as to the identities and types of phospholipid and especially the surface active agent or agents should be expected depending upon the water-insoluble or poorly water-soluble biologically active substance selected as the surface properties of these small particles are different. The most advantageous surface active agent for the insoluble compound will be apparent following empirical tests to identify the surfactant or surfactant system/combination resulting in the requisite particle size and particle size stability on storage over time.
[0034] Appropriate choice of stabilizers will prevent flocculation in the aqueous phase. The surfactant is chosen to be active at the compound water interface, but it is not chosen to be active at the carbon dioxide-organic solvent or carbon dioxide-drug interface. It is not necessary for the stabilizer to be soluble in CO2; it can be soluble in the liquid to be sprayed, as it only needs to be active at the CO2/solute interface.
[0035] This invention provides a supercritical fluid/compressed fluid based process to produce suspensions of water insoluble drugs with an average particle size of less than 100 nm and a narrow size distribution. An essential element is the use of phospholipids and other surfactants to modify the surface of the drug particles to prevent particle aggregation and thereby improve both their storage stability and pharmacokinetic properties.
[0036] Materials and methods: Particle sizing was based on the principle of photon correlation spectroscopy using Submicron Particle Sizer-Autodilute Model 370 (NICOMP Particle Sizing Systems, Santa Barbara, Calif.). This instrument provides number weighted, intensity weighted, and volume weighted particle size distributions as well as multimodality of the particle size distribution, if present.
[0037] Separation and quantitation of cyclosporine was carried out with a Waters HPLC system utilizing reverse phase chromatography. The drug was extracted from the sample with methanol and injected for analysis on a C-18 analytical column at 60-80� C. with a mobile phase consisting of acetonitrile, methanol, and water. Anylate was detected though its absorbance at 214 nm. Operation of the chromatography system and data processing was conducted by Waters Millennium v2.1 software.
[0038] Carbon dioxide was used to prepare rapid expansion supercritical solutions since there is no literature reference to any chemical interaction with cyclosporine. Carbon dioxide has been used as a solvent for cyclosporine in fermentation recovery and in HPLC. The relative solubilities of cylclosporine dissolved in a solvent that is expanded with compressed carbon dioxide will be established.
[0039] A gas will approach sonic terminal velocity when expanded in a nozzle. Therefore it is important to determine the maximum nozzle diameter and aspect ratio (L/D) that will maintain these conditions in scaleup. Nozzle diameters of 10-50 microns are reported to be used in conjunction with aspect ratios ranging from 5 to 200.
[0040] The apparatus for rapid expansion from supercritical solution shown in FIG. 1 included a high pressure vessel 1 for formulating the drug/CO2 solution. Because the drug solution was isolated from the pressurizing fluid by the piston 2 and the valve 2 a, the concentration of the drug was constant during the spray. The solution was mixed with a stir bar 14 a and a magnetic stirrer 14. The temperature was controlled with heating tape 4. The pressure on the piston and hence the drug solution was controlled via line 3 by an automated syringe pump 5 (ISCO model 100DX) containing pure carbon dioxide.
[0041] The preheater as shown in FIG. 2A consisted of a hole (0.030″ i.d. and 4″ long) 8 a bored axially along the center of a 2″ o.d.�0.030″ i.d.�4″ long copper rod to preheat the solution to a desired temperature before expansion. The preheater assembly 8 and the expansion valve 7 are connected to the high pressure vessel 1 via outlet tube 6. The assembly 8 and the expansion valve 7 were heated with high temperature heating tape 12 and were highly insulated. To monitor the temperature, a thermocouple 13 was placed directly into the preheater assembly close to the orifice.
[0042] The expansion nozzle as shown in more detail in FIG. 2B included a 0.254 mm thick, 30 micron diameter laser-drilled orifice 11 (length to diameter ratio �8.5), which was placed between two copper gaskets 15 (10 mm o.d., 6 mm i.d. and 1 mm thick) and sealed in a �″ tubing assembly. The downstream end of the orifice was counterbored into a V-shape as shown in FIG. 2B to prevent the expanding jet from hitting the walls and distorting the morphology of the precipitating solute. To prevent plugging of the orifice, a �″ inch diameter, 0.5 micron metal filter 9 was inserted upstream of the nozzle preheater assembly (FIG. 1). In addition, a bypass line 10 was used to pre-pressurize the preheater assembly with pure solvent (CO2) before each spray, otherwise the initial pressure drop across the filter would precipitate the drug and plug the orifice 11. After displacing pure solvent from the preheater, the orifice was submerged into 25 mL aqueous solution in order to trap and stabilize the precipitating drug microparticles. The high kinetic energy of the jet forced the spray 2 cm below the surface of the aqueous phase.
[0043] The apparatus used to carry out the Compressed fluid antisolvent sprays is shown in FIG. 3. A 300 mL high pressure vessel 16 equipped with a magnetically coupled agitator (Parr) depicted in outline above vessel 16 was used to precipitate the drug. Prior to spraying the drug solution, 50 mL of aqueous solution was added to this precipitator. The aqueous solutions were either pure water, 1.0 wt % Tween 80 in water 10 wt % phospholipid dispersion in water or 10 wt % phospholipid dispersion with 2.0 wt % Tween 80 in water. Phospholipid and phospholipid plus Tween-80 dispersions were made by high shear homogenization of their aqueous suspension by passing through a microfluidizer (model M110EH, Microfluidics). Tween-80 was purchased from ICI and egg phospholipid was from Pfansthiel. Aqueous sodium hydroxide solution (1N) was used to adjust the pH of these dispersions to 7.5. Carbon dioxide was compressed with a Haskel air driven gas booster 17 (model AC-152), regulated with a Tescom pressure regulator (model 26-1021) 18 and monitored by pressure gauge 19. The CO2 pressure was monitored to within �0.2 bar. A water bath with a recirculator 30 was used to control the precipitator temperature. The solution was sprayed through 50 micron i.d. fused silica capillary tubing 27 (Polymicro Technology) with a length/diameter ratio of 2800. To maintain a constant flow rate, the solution was pumped through the solution valve 28 to the capillary atomizer using an automated syringe pump 20 (ISCO model IOODX).
[0044] A 0.5 μm filter 21 was threaded into the CO2 effluent line 22 to prevent loss of the water insoluble compound from the precipitation vessel. The filter assembly included an in-line sintered filter element (Swagelok �F� series) which was welded onto a �″ i.d. NPT fitting. The effluent vent valve 23 (Whitey, SS-21RS4) connected to rotameter 24 was heated in a water bath 29 to at least 50� C. to prevent the expanding CO2 from freezing. During precipitation, a known amount of aqueous solution 25 was agitated using a 45� pitched blade impeller 26. After precipitation, agitation was discontinued and the vessel was isolated to depressurize for 30-45 min. The aqueous solution was then recovered for particle size analysis.
[0045] Unless otherwise specified, all parts and percentages reported herein are weight per unit volume (w/v), in which the volume in the denominator represents the total volume of the system. Diameters of dimensions are given in millimeters (mm=10−3 meters), micrometers (μm=10−6 meters), nanometers (nm=10−9 meters) or Angstrom units (=0.1 nm). Volumes are given in liters (L), milliliters (mL=10 −3 L) and microliters (μL=10−6L). Dilutions are by volume. All temperatures are reported in degrees Celsius. The compositions of the invention can comprise, consist essentially of or consist of the materials set forth and the process or method can comprise, consist essentially of or consist of the steps set forth with such materials.
[0046] While the invention has been described in connection with what is presently considered to be the most practical and preferred embodiment, it is to be understood that the invention is not to be limited to the disclosed embodiment, but on the contrary, is intended to cover various modifications and equivalent arrangements included within the spirit and scope of the appended claims.
[0047] The following examples further explain and illustrate the invention:
[0048] Cyclosporine Microparticle Formation by the Rapid Expansion from Supercritical Solution Process
[0049] A homogeneous solution of cyclosporine in supercritical CO2 was expanded by rapid expansion from supercritical solution into various aqueous solutions to study microparticle stabilization. The aqueous solutions were pure water 1.0 wt % Tween 80, phospholipid dispersion or 2.0 wt % Tween 80 with phospholipid dispersion. An amount of 0.0480 g of cyclosporine was charged to a variable volume view cell and 20 mL of CO2 were added to formulate a 0.25 wt % solution. After the solution came to thermal equilibrium (T=35� C.) the cyclosporine/CO2 solution at 3000 psia was sprayed through a 0.30 μm orifice (L/D of 8) into an aqueous solution for 25 seconds. The pre-expansion temperature was 40� C. The volume weighted particle size of the cyclosporine microparticles expanded into pure phospholipid was 153.7 nm (peak 2) as shown in FIG. 4. Most of the mass that constitutes the peak 1 of 20-50 nm diameter may originate largely from the phospholipid; however, this population may also possess some particles that contain cyclosporine. The volume weighted mean particle size of the cyclosporine microparticles expanded into phospholipid dispersion with 2.0 wt % Tween 80 was 80.9 nm (peak 2) as shown in FIG. 5. In this case again the smaller peak (26.8 nm) may originate largely from the phospholipid and Tween 80 dispersion and a small fraction of cyclosporine containing particulates. A control experiment was performed in which pure carbon dioxide at 3000 psia was sprayed into the phospholipid dispersion. The mean diameter of the particulates in the dispersion was 9 nm. Therefore, the particles greater than 100 nm in FIGS. 4 and 5 were not originating from purely the phospholipids, but were drug microparticles. Similarly, for the phospholipid dispersion with 2 wt % Tween 80, the mean diameter of the was 28 nm.
[0050] Water Insoluble Compound Phase Behavior in Compressed CO2.
[0051] In order to assess whether a particular water insoluble compound should be processed by rapid expansion from supercritical solution or compressed fluid antisolvent, the solubility of the candidate drugs in carbon dioxide was measured. Cyclosporine, nifedipine, piroxicam, carbamazepine, indomethacin and tetracaine HI were studied. To prepare solutions with a constant molar composition, measured amounts of drug and CO2 were charged to the variable volume view cell from Example 1. To increase the solubility, a cosolvent, i.e., acetone or ethanol, was added to the view cell. The temperature and pressure were varied from 25-45� C. and 1200 to 4500 psia, respectively. The phase behavior was determined visually by noting when phase separation occurred as the pressure was slowly reduced at 1-2 psia/sec. Table I shows a summary of the solubility behavior in CO2. Cyclosporine was soluble in CO2 up to 0.5 wt %. Solutions containing 0.01 wt % carbamazepine, tetracaine HI, nifedipine and piroxicam were insoluble in CO2. With the addition of 2.40 wt % acetone, 0.026 wt % piroxicam was soluble in CO2 at 25� C. for all pressures down to the vapor pressure of CO2, which is 930 psia. A solution containing 0.028 wt % nifedipine and 2.26 wt % acetone cosolvent was insoluble in CO2 at 25� C. At 45� C., the nifedipine was solvated with no visible phase separation down to 2000 psia.
[0052] Indomethacin Microparticle Formation by the Compressed Fluid Antisolvent Process
[0053] A 9.9 wt % solution of indomethacin in acetone was sprayed into carbon dioxide with the aqueous solution using the Compressed fluid antisolvent process. The duration of the spray was 30 s at 1 mL/min. The volume weighted mean particle size of the phospholipid dispersion was 26 nm (peak 1) as shown in FIG. 6. A bimodal size distribution was observed for the indomethacin particles with mean diameters of 143.0 nm (peak 2) and 1088.9 nm (peak 3), respectively. Particles with such a size difference are easily separated by filtration. For the microparticles precipitated into phospholipid dispersion in the presence of 2.0 wt % Tween 80, the volume weighted mean particle diameter was 126 nm as shown in FIG. 7.
[0054] Tetracaine HI Microparticle Formation by the Compressed Fluid Antisolvent Process
[0055] A 0.97 wt % solution of Tetracaine HI in acetone was sprayed into the precipitator containing carbon dioxide and pure water. The volume weighted mean particle sizes of the Tetracaine HI microparticles were 31.8, 193.4 and 2510.1 nm, respectively (FIG. 8). This illustrates that the Compressed fluid antisolvent process can produce extremely small particles even without surfactant stabilizer. With 1.0 wt % Tween 80 added to the water, three peaks were observed with mean diameters of 9.5 nm, 38.3 nm and 169.1 nm (FIG. 9). The particle size distribution for 1.0 wt % Tetracaine HI stabilized with phospholipid dispersion and 2.0 wt % Tween 80 is shown in FIG. 10. A monomodal distribution is observed between 8-200 nm with a mean diameter of 27.3 nm. This peak includes both the surfactant aggregates and drug particles. No drug particles above 200 nm were observed.
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I found this recipe on a box of Kelloggs low fat granola with raisins cereal. It's my family's favorite store bought granola so I think they'll love these muffins too.
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