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33 year old man | Lutherville, MD, USA | Seeking women 18-32 in Baltimore, Maryland, United States
My name is John Aumiller and I am looking forward to meeting you!! Trust me I am worth it!! Lets get together some time!!
I am a pretty laid back guy for the most part.......I also enjoy doing a lot of independent activities. Don't get me wrong I do enjoy socializing with family and friends and going out when I can. I also really enjoy trying new activities in which I have never tried before. I am a very open-minded person as well. I also believe that perserverance is important in everything you attempt or actually attain in life. As far as what I am looking for in an indivual of the opposite gender is a kind warm-hearted person. I would like a person that appreciates me for the person that I am. I want someone who is honest as well as compassionate that takes other people's feelings into consideration. I hope I can find someone that is willing to be a risk taker and try different activities. It is also important that the individual does not take themselves' to seriously and is willing to find light in any given situation that comes upon them. It is also importan that this individual is self-assured and is ability to think for themselves'. I would like to find someone is independant rather than dependant on me all of the time. I think a strong balance of oneself is essential for any human being to have as well as maintain a healthy lifestyle.
Coffee and conversation , Cooking , Dining out , Museums and art , Music and concerts , Exploring new areas , Nightclubs/Dancing , Playing sports , Political interests , Travel/Sightseeing , Watching sports , Wine tasting
Aerobics, Baseball, Basketball, Billiards / Pool, Bowling, Cycling, Dancing, Football, Golf, Running, Skiing, Swimming, Tennis / Racquet sports, VolleyBall, Yoga
I exercise 1-2 times per week.
Don't display my sign
I like Dogs, Exotic Pets, Fish
Middle of the Road
I love to go to go hang out in Federal Hill or the Towson area. I love going to the beach or traveling within the United States as well as out of the country such as places like Canada or Mexico!
Salisbury University, Salisbury, MD
I love Rock'n'roll especially 80's music, I like to watch the office and Law and Order as well as watch anything funny whether on televison or the movies.
I like to read watch movies.......Do adventerous activites like skiing hiking as well as mountain biking! I enjoy socializing with friends! I also love to go to Ravens games when I have the chance!
"The Illiad" by Homer as well as "The Race"
Z{{Cta}} {{#if HasMoreInfo}} ?{{CtaSecondary}} {{/if}}
|What he is looking for
|6'1" (185cms)
|5'6" (167cms) to 5'10" (177cms)
|Body type:
|Athletic and toned
|Slender, About average, Athletic and toned
|No preference
|Light brown
|No preference
|No preference
|No preference
|Medical / Dental / Veterinary / Fitness
|No preference
I am a medical technician.......Take lasers to different hospitals in the mid-atlantic region and operate for the surgeon in the O.R
|$25,001 to $35,000
|No preference
|Never Married
|Never Married, Divorced
|Have kids:
|Yes, and they live at home
|Wants kids:
|White / Caucasian
|White / Caucasian
|Christian / Protestant
|Christian / Catholic, Spiritual but not religious, Christian / Other
|Bachelors degree
|Associates degree


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Ratings game
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June 19 2009, 04:32 AM
Guy Gardener
Fleet Admiral
Location: In the lap of squalor I assure you.
Re: Ratings game
Hmmm? You saw the mirror universe Episodes? If they wanted Nana Visitor to play it for cheep thrills for loons who can only think with their pants, she could have done it sans boobies or not. Further more, now what the attendant wore, that was provocatively garish. What they had Seven wearing reminded of 12 year old Jake Sisko's casual attire more so than any bunny that done escaped from Playboy Mansion.
"Glitter is the herpes of arts and craft."
Troy Yingst. My Life as Liz
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- SCU Business Home
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Undergraduate and graduate students get a professional business education, the technical skills necessary for success, and the ethical, global, and humanistic perspectives that are hallmarks of a Jesuit education.
Two Business School faculty receive Hackworth Grants
Congratulations to professors Hoje Jo and William Sundstrom for receiving Hackworth Grants from the Markkula Center for Applied Ethics.
2015 Silicon Valley Boomer Venture Summit Business Plan Competition
Six entrepreneurs targeting the 45+ demographic will present their business plans in a competition at the annual Silicon Valley Boomer Venture Summit on Tuesday, June 30, in Santa Clara University's Recital Hall.


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Marvel's Daredevil features a beautiful red opening title sequence. Red is Daredevil's signature color, so you think the entire show would be drenched in it, but excepting the opening titles, it's not. The color palette of the show is a base of blue and black, with highlights of sodium yellow and bilious green. Shadows are deep and stark, often creating frames like comic book cells, with what little is revealed by the stark lighting cast in sickly, sallow tones. Hell's Kitchen is not a welcoming place—this is not Tony Stark's sun-drenched Malibu or the gleaming, bright world of the Avengers. The streets Daredevil patrols are murky and darkness looms around the edges of the frame, obliterating what little light trickles down to the street.
A World On Fire: The Recurrence of Red in Marvel's DaredevilPosted in Reviews, TV with tags Applied color theory 101, If Daredevil looks at fire does it blind him?, Marvel's Daredevil, Red, Superheroes on tv on April 16, 2015 by Sarah
Of The People: Daredevil, the Devil, and street-level heroesPosted in Reviews, TV with tags Daredevil is of the people for the people by the people, Marvel's Daredevil, Superheroes on tv, The devil and Matt Murdock on April 15, 2015 by Sarah
Now that we've talked about Daredevil as a television show, let's talk about Daredevil as a person. Or rather, let's talk about Matt Murdock, because over the course of the show we see that Matt and his vigilante alter ego are one and the same. Matt Murdock is inspired to don a mask and become a vigilante because he sees injustice and fear oppressing the good people in Hell's Kitchen, but when he is "in character" as Daredevil, he's no less Matt Murdock than he is when he's arguing for justice in a court of law. Throughout the show we see Matt struggle with his conviction not to kill, and ultimately he upholds his morals, turning Wilson Fisk over to the police. Matt's morality, and his Catholic faith, are important parts of his identity which he does not subsume in order to fight crime.
The TV Superhero We Need AND Deserve: Marvel's DaredevilPosted in Reviews, TV with tags Charlie Cox, Don't get me started on Rosario Dawson, Marvel's Daredevil, Superheroes on tv, Vincent D'Onofrio on April 14, 2015 by Sarah
Last Friday was the long-awaited premiere of Daredevil, the first of Marvel's Netflix series which will ultimately culminate in a Defenders miniseries along about 2017. The first of the "street-level" superheroes, Daredevil is charged with essentially being the Iron Man of the Defenders, responsible for setting the tone and style for the whole team. And man, did Daredevil ever deliver. Taking advantage of Netflix's native binge-watching environment, series creator Drew Goddard (Cabin in the Woods) and showrunner Steven S. DeKnight (Spartacus) offer a tightly plotted, highly serialized season meant to be consumed in large chunks. With all 13 episodes available at once I wondered how best to review Daredevil, and ultimately decided to tackle it in three parts, with this first review concentrating on the overall tone of the show itself. If you'd like episodic recaps, here's a good set.
Spring Movie Preview: April 2015Posted in Movies, Previews with tags April movies, Countdown to summer, Fucking Paul Blart AGAIN, Spring movie preview on April 2, 2015 by Sarah
April 3
Furious 7
Perpetual motion has been discovered and it's this franchise that will never stop never end never go away.
Spring Movie Preview: March 2015Posted in Uncategorized on March 5, 2015 by Sarah
March 6
Neill Blomkamp remakes Short Circuit in a movie critics like even less than Blackhat.
Fashion Friday Fun Post: Oscars 2015Posted in Celebrities, Event with tags Fashion Friday Fun Post, GOD DAMN CHRIS EVANS, JFC Scarlett Johansson, Oscar fashion, Red carpet fashion on February 27, 2015 by Sarah
Bee Shaffer in Dolce & Gabbana is actually my best dressed of the night. I LOVE this floral gown and her styling, and I especially love that Anna Wintour's face seems to have frozen in that expression. Marion Cotillard in Dior gets "best white of the night", while Lady Gaga in Azzedine Alaïa is both appropriately weird and occasion-appropriate. Lupita Nyong'o's purloined Calvin Klein pearl dress is worth discussing, at least, and Meryl Streep in Lanvin and Tegan & Sara all had great menswear-inspired looks.
TV Recap: Agent Carter 1.8Posted in Reviews, TV with tags Agent Carter, Bow before Peggy Carter, Marvel still has a TV problem, TV recap, Winter Soldier end game on February 25, 2015 by Sarah
Marvel's Agent Carter ended last night, without confirmation of a second series, so for now this is it for Peggy Carter and the SSR. In many respects, it was a satisfactory ending. Peggy comes to terms with the loss of Steve Rogers, Howard Stark deals with his own destructive nature and legacy, and the SSR accepts Peggy as one of their own—though the accolades for the resolution of the Howard Stark situation goes to Agent Thompson, not Peggy. But as Peggy says, she doesn't need public recognition—she knows her value. All she's wanted is to be allowed to do the work, and that is what she gained during her first year with the post-war SSR: The ability to be an effective member of a team.


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A collection of news and information related to Upton Sinclair published by this site and its partners.
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Friday @ 5: A cocktail to kick off the weekend
CAFO protection law passes in Iowa, Illinois hearings held Wednesday
Musician's design hits right notes [Corrected]Story | Dec 24, 2011 | 5:03 PMFor University High School, money does grow on trees. -------------------- FOR THE RECORD: An earlier version incorrectly stated the number of votes Lisa Xie's design got. It was 445, not 445,000. -------------------- At least, it does now since a...
The poetry of discussion
Don't be agast (or even aghast)! Tribune once trifled with standard spelling
'Hog butcher for the world'
PST, A to Z: 'Eames' at A+D Museum, 'Sympathetic' at MAK CenterStory | Oct 11, 2011Text is a central component of two Pacific Standard Time exhibitions, both focused on design: "Eames Designs: The Guest Host Relationship" at the A+D Museum, and "Sympathetic Seeing: Esther McCoy and the Heart of American Modernist...
Former columnist Bill Granger dies at 70Story | Apr 23, 2012From Daily Herald columnist Burt Constable's obituary: William F. "Bill" Granger, a former Daily Herald columnist, was 70 years old when he died Sunday night at the Manteno Veterans' Home, where he had lived since March 2002. But loved ones,.....
88 books that shaped America, at the Library of CongressStory | Jul 4, 2012The Library of Congress' list of 88 books that shaped America includes poetry, novels, nonfiction, a play, a polemic, books of science and grammar, cookbooks and children's books. What's it missing?...
The Net and the news
'There Will Be Blood'


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"I chose red for the background and it came out perfect. The images turned out great and the customer service rep that assisted me was so nice. I made some last minute changes and she catered to it without any issues. The people who received the cards loved them!"
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"I really loved the design of this card! The dress is just beautiful against the soft pink background with the gold accents! Everyone LOVED it!"


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Don Vito Net Worth: Don Vito is a producer, songwriter, composer, engineer, director and entrepreneur who has a net worth of $500 thousand. Born Rodney Richard on July 9, 1978, in Gary, Indiana, US, he has taken part in numerous high-ranking projects via his music & video production company, Don Vito Productions. The ones that earned him prominence among audiences are his collaborations with Kandi...
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Video stream: http://www.twitch.tv/takkynoko
Join the stream chat
Forum thread
Thread / Wiki
Hope everyone's having a good Friday!
No Wizard or Kyouryuu next week. Everyone take a siesta!
Thread / Wki
The first time I saw this movie I knew it was something I wanted us to translate. But I figured that since it was released by Warner Brothers, there is still a large following in the US and that there was actually a movie premier in the US that this movie was bound to get licensed. But as time passed, and there was no information about a US release, even though it had been licensed in like 60 other countries, I told myself that if a year passed since the Blu-Ray release date and there still was no information, I would translate it myself.
Well, it's been over a year, and so I'm proud to bring you the awesomeness that is the Rurouni Kenshin live action movie. I'd like to thank Azazel for timing this hideously long movie and managing to figure out how to properly rip and encode it, Yaiba, for making an amazing karaoke for the MV, and our wonderful QC team who hopefully caught all of my mistakes, especially the really stupid ones.
Even if you've never heard of Rurouni Kenshin before, give it a try, I can guarantee you won't be disappointed.
Stuff to know:
So yeah, Satou Takeru has come a long way from Den-O, hasn't he? If you love Kenshin the anime/manga or Den-O, do check this out. It's a fun historic Japan movie.
Big thanks to Luna for heading this project. Probably wouldn't have been done without her.
If you're a newcomer to the series or just want to know more about the real Japanese history behind the movie, check out our wiki page about it:Our Kenshin wiki page
Let me know if there are any other terms or historical stuff that you'd like us to clear up.
Special guest of Silver as Gray!
Thread / Wiki / Artist
Looks like they're all seeded except Fourze 15-30 sd. Might be missing this file
Also, check out the page listing unseeded torrents
And the Bittorrent seeding request forum
Hey, Kouga! I guess this was for some Garo event? I've been holding onto this for quite a while.
Yet another batch. Remember to resume if possible.
Also, if you're feeling generous with bandwidth, I should plug the
Torrents that need seeds page
It's been a while, so it's probably worth covering this again.
If you have ANY files that are in the batch, it's worth it to START the batch. STOP the batch. Copy/cut the files you already have into your torrent directory. Then START the batch over again so it rechecks for the new files.
The reason you'd want to do it this way is so that it doesn't download those files again and helps upload those files to the swarm.
If you were on the torrents that were deleted, please move your partial files over so that it can be resumed in the batch torrent.
Remember that with torrents, it doesn't matter if the file is corrupt. Torrents can patch files for you, so they're super handy.
Come! Let us partake in jolly co-op!
Man, a lot of stuff happened around this time.
Maybe it'll have seeds, maybe it won't! But seriously though, I'm just tossing up batch torrents. It might take a while for stuff to get seeded as people rediscover the batches and help seed them.
Kind of relying on the community to come out and help seed for these (especially for the older series which have less interest for them)
Thread about batching stuff
So this one isn't our release. We're just hosting it. (We did contribute some of the files for them though).
The video just released is compilation of anime mecha openings for the first decade of the 2000s. It's about 2.5 hours long (If you watch with media player classic, use the chapters).
Check out his site: http://lookingglass.kokidokom.net/
We realize that Galaxy Force is in there twice and that there are other things that can be tweaked, but I think it's fine for what we were going for. Please enjoy!
Youko: J, what's kissing?
J: It's what Jin and Kei are always doing.
Youko: Where?
J: Where Youko can't see.
Also included:


text:
|Project Name
|Price (USD)
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|Price (USD)
|convert photoshop into HTML/CSS
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|Convert Photoshop file into HTML and CSS
|...whole site and only require this to be cut in HTML and CSS. We would also like a collapsible accordion
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|Convert Photoshop layout to html/css
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|Photoshop/Fireworks to HTML/CSS
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|Website Design
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|Photoshop to HTML
|...a freelancer to convert my Photoshop (PSD) template into the equivalent HTML and CSS based coding. The
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|Photoshop to HTML/CSS
|We need to convert a home page and a inner page from psd to xhtml valid. The following are required: ...Font-Face Fonts 4. No table layouts, must be fully CSS layout 5. Final site must be optimal for viewing
|Website Design, PSD to HTML, HTML, jQuery / Prototype
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|Convert Photoshop PSDs to HTML
|...looking for someone that can convert provided Photoshop PSD files into html / CSS. There are two PSDs, one...1. W3C Valid XHTML 1.0. 2. Strict Table-less CSS markup with good separation of content and style...bidder must provide two completed HTML templates, one corresponding CSS file, and all of the necessary images
|Javascript, Website Design, Graphic Design, Photoshop
|May 1, 2008
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|Photoshop to html and css
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|Convert Photoshop layouts to HTML
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|PHP, Windows Desktop, Linux, Engineering, Photoshop, CSS, Software Architecture, Mac OS, Software Testing, Chrome OS, MySQL, UNIX
|Feb 22, 2007
|Feb 22, 2007Ended


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36 year old man | Bixby Knolls, CA, USA | Seeking women 28-38 within 25 miles of Long Beach, CA
Active within 5 days
I'm a mellow guy from Long Beach, but I also...
I'm a mellow guy from Long Beach, but I also know how to have a good time. I love to travel and occasionally get lost, but that's the best way to get to know a new place! My family is really important to me and there's never a shortage of fun when we all get together. I play on a few soccer teams at times throughout the week with my friends, depending on the time of year, so I'm a pretty active guy. I discovered snowboarding 3 years ago while working for a snowboarding company so I'm praying for snow this season. I also like to go hiking and exploring new cities. I would definitely prefer a fun dinner, with family or friends, over a loud bar these days. I have been working on my house for the last year and a half and cannot wait till it's done in the next few months to host fun events with family and friends when I'm not out traveling. As for who I'm looking for. It'd be great if they were active! I definitely want to travel and explore wherever I can go. I have traveled to several countries (Spain/family there, Italy/family there, Germany, Switzerland, France/family there, and England, but still want to see more. One goal is to watch a soccer game in Europe! I'm making a list of different countries to travel to over the next few years. It would be amazing if I could create some experiences traveling with someone and come back with some funny stories to share with family, and friends. Couple of random facts: Earned my degree in Elementary Education and worked with Special Ed Pre-K/K during college Accidentally discovered relatives in Sicily, standing right behind us, who were wondering what these Americans were doing in their little town Definitely love road trips. Hoping to take a few this winter to go snowboarding. I'm known in my family to be the one who makes the travel to visit relatives for family events regardless of the geographic location. I frequent traveling to MI because of relatives, but I'll be traveling more to NC and CO now to see my sis and other family. It's a great way to experience new locations when you can couch surf. :) I like to keep busy whenever possible, but definitely enjoy my down time with fun dinners and movie nights. My motto is: Have bag, will travel!
Camping , Coffee and conversation , Cooking , Dining out , Movies/Videos , Museums and art , Music and concerts , Exploring new areas , Nightclubs/Dancing , Performing arts , Playing sports , Travel/Sightseeing , Video games , Volunteering , Watching sports , Wine tasting
Billiards / Pool, Bowling, Other types of exercise, Soccer, Walking / Hiking, Weights / Machines
I exercise 3-4 times per week.
I like Cats, Dogs
I go to some local happy hours occasionally over on 2nd St, Pine Ave and among other places. I work in Orange County so I do a lot of social stuff in that area after work.
California State University, Long Beach, Long Beach, CA
I play on some soccer teams with my friends, watching movies. It's great to meet up with friends for dinner & drinks. I prefer that now to going to bars, but that's still fun once in a while. I started snowboarding 3 years ago. Laughing & goofing off
For fun I enjoy hanging out with friends and family. I enjoy going to sporting events, happy hours, dinner and drinks, playing soccer with my friends, and so on.
Z{{Cta}} {{#if HasMoreInfo}} ?{{CtaSecondary}} {{/if}}
|What he is looking for
|5'7" (170cms)
|4'11" (149cms) to 5'10" (177cms)
|Body type:
|A few extra pounds
|Slender, About average, Athletic and toned, A few extra pounds
|No preference
|No preference
|No Way
|No Way, Yes, but trying to quit
|Social Drinker
|Never, Social Drinker, Moderately
|Technical / Science / Computers / Engineering
|No preference
|$50,001 to $75,000
|No preference
|Never Married
|No preference
|Have kids:
|No preference
|Wants kids:
|Asian, White / Caucasian
|Asian, Latino / Hispanic, Middle Eastern, Native American, Pacific Islander, White / Caucasian
My mom is from Vietnam and my dad's side originates from Sicily. I could never do the carb-less diet. I wouldn't be able to survive without rice, bread, or pasta!
|I'll tell you later
|No preference
|No preference
|Bachelors degree
|No preference
I earned a degree in Liberal Studies with a concentration in Language and Literacy. My intention was to become an elementary school teacher, but I ended up doing I.T., which has been a great experience and a lot of fun for me.


text:
Home energy problems can lead to high utility bills, mold and mildew, cold floors, drafts, excessive dust, air leaks, condensation, and rooms that are too cold or too hot to live in. They can also produce allergies, headaches and other health complaints. The underlying causes of these symptoms are not always easy to see. Before you spend your dollars on energy improvements, it makes good economic sense to find out which system needs work, first. We help you make a plan, then prioritize.
Contact us at 631-813-4446 or firstname.lastname@example.com for a free consultation.


text:
'Secure Communities': Mandate or Not?
The feds say participation in the "Secure Communities" initiative is voluntary, but can cities really opt out?
The latest local immigration enforcement program from Immigrations and Customs Enforcement, Secure Communities, is billed by the federal government as a voluntary partnership between Washington and state and local governments. As part of the initiative, when a criminal is booked by a participating agency, his fingerprints are sent to a federal immigration database to see whether they're in the country illegally. If there's a match, ICE will determine whether to deport that person. Secure Communities is supposed to blanket every city, county and state by 2013.
But some cities are questioning just how "voluntary" this partnership is.
Some local officials have raised concerns that the program doesn't actually "remove the most dangerous criminal aliens from the United States," which is its stated goal. Rather, they argue, it targets immigrants who have committed minor offenses, or none at all.
Regardless of their reasons for wanting out, though, cities are finding that participating in the program is harder to avoid than they expected. From the Huffington Post:
In an August document titled "Setting the Record Straight," ICE seemed to deny that any ambiguity existed. For the first time, the agency vaguely outlined how a city or county could avoid joining. The document states that if a jurisdiction wants to opt out, various stakeholders will meet to "discuss any issues and come to a resolution, which may include...removing the jurisdiction from the deployment plan." To date, no city has successfully been able to do this. But San Francisco may be the first; this week, Sheriff Hennessey sent a letter to DHS officials reiterating the city's request to exit the program. And just yesterday, leaders from two other California counties followed suit. ICE officials are reportedly considering this appeal.
San Francisco could turn out to be a test case for whether this program is really a mandate or not.
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BPL Community Profile
Richard Nisley (richard295) - BPL Premium Member
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All Forum Posts by Richard Nisley
Re: Re: Richard Nisley's reference
Ivo, You said in part, "Elsewhere Richard mentions this in more detail, suggesting that it might add around 0.3 clo to the ensemble, and could go up to 0.6 clo... Unfortunately, This is not...
Re: Re: Re: Re: Re: Re: Re: Re: Re: Windshirt Experts
William, MVTR is the term primarily used to describe how much moisture you can move through a solid membrane via Brownian Molecular Movement. There are at least six different tests that don'...
Re: in practice
Connie, CAMP wind shirt = Mountain Hardwear Ghost Whisper Anorakwind shirt = ZPacks wind shirt The above will all pass water vapor at about the same rate as a quality rain jacket; they will n...
Re: Re: Re: Re: Re: Re: Re: Windshirt Experts
Charlie, You said, " Basically, should I believe that "wicking" is pure BS and CFM the *only* factor I should consider for sweat management?" Wicking is pure BS for DWR c...
Re: Re: Re: Re: Re: Montbell Ex Light Anorak- A Contrarian View
Steve, This chart shows a higher density range so that you can see the down's performance knee (major slope change) begin:
Re: Re: Re: Montbell Ex Light Anorak- A Contrarian View
Steve, Up to ~2-2.5x density (half the loft but the same amount of down) in jacket baffles is fine. Laying on it will take you way beyond the linearity point; quilts are smart (smile). ...
The Colors of Truth
Aaron, You said, "I don't know where you get the 16% increase in insulation?" The thermograph's colors are my attempt for non-experts to intuitively compare garments thermal p...
Montbell Ex Light Anorak- A Contrarian View
I have both lab tested and field tested many Montbell down garments over the years and have routinely found them to have extraordinary value. Coming from that perspective, I was surprised to read n...
Re: Specs
These are the specifications for the jacket I am selling: The size large weight is 27.2 oz. The DWR is perfect and has never been modified. These are the specifications for the cu...
Re: Which year is it?
It is a Fall 2008 model that has been in storage. It has the stiff water repellent zipper rather than the current plastic teeth zipper. You have to pull the bottom tab down while you pull top tab up.
All Reader Reviews by Richard Nisley
Showing 1 - 2 of 2 | Page: 1
Lite my fire firesteel scout firelighter
I went back to the Midwest, this month, for a family reunion and fishing trip. I took my fire steel with me. My two nephews are 10 and 12 and they love to fish. The 12 year old asked me if I would tea...
Jetboil Personal Cooking System
My piezo failed after a couple of days. It took one second to fix it by bending down the ignitor rod to make a slightly smaller gap (1/8" smaller). I then used it in Alaska for 1 1/2 months twice a da...


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Controlled-release preparations of oxcarbazepine and derivatives thereof for once-a-day administration are disclosed. The inventive compositions comprise solubility- and/or release enhancing agents to provide tailored drug release profiles, preferably sigmoidal release profiles. Methods of treatment comprising the inventive compositions are also disclosed.
1. A method of treating seizures comprising administering to a subject in need thereof a pharmaceutical formulation comprising a homogeneous matrix comprising:
(a) oxcarbazepine;
(b) a matrix-forming polymer selected from the group consisting of cellulosic polymers, alginates, gums, cross-linked polyacrylic acid, carageenan, polyvinyl pyrrolidone, polyethylene oxides, and polyvinyl alcohol;
(c) at least one agent that enhances the solubility of oxcarbazepine selected from the group consisting of surface active agents, complexing agents, cyclodextrins, pH modifying agents, and hydration promoting agents; and
(d) at least one release promoting agent comprising a polymer having pH-dependent solubility selected from the group consisting of cellulose acetate phthalate, cellulose acetate succinate, methylcellulose phthalate, ethylhydroxycellulose phthalate, polyvinylacetate phthalate, polyvinylbutyrate acetate, vinyl acetate-maleic anhydride copolymer, styrene-maleic mono-ester copolymer, and Eudragit L100-55 (Methacrylic Acid-Ethyl Acrylate Copolymer (1:1)), and methyl acrylate-methacrylic acid copolymers.
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This application is a Continuation of U.S. application Ser. No. 11/734,874, filed Apr. 13, 2007, which claims priority to U.S. Provisional Application No. 60/794,837, filed Apr. 26, 2006, the disclosure of which is incorporated herein by reference in its entirety.
The present invention is directed to controlled-release preparations of oxcarbazepine and derivatives thereof for once-a-day administration.
Oxcarbazepine belongs to the benzodiazepine class of drugs and is registered worldwide as an antiepileptic drug. Oxcarbazepine is approved as an adjunct or monotherapy for the treatment of partial seizures and generalized tonic-clonic seizures in adults and children. An immediate-release (IR) formulation of oxcarbazepine is currently on the market under the trade name Trileptal� and is administered twice a day to control epileptic seizures. Such immediate release compositions provide the drug to the patient in a manner that result in a rapid rise of the plasma drug concentration followed by a rapid decline. This sharp rise in drug concentration can result in side effects, and make multiple daily administration of the drug necessary in order to maintain a therapeutic level of the drug in the body. The need for a controlled-release dosage form for drugs taken chronically such as oxcarbazepine and derivatives is self-evident. Patient compliance is greatly improved with controlled-release (CR) dosage forms that are taken, for example, once-a-day. Also, there are significant clinical advantages such as better therapeutic efficacy as well as reduced side effects with controlled-release dosage forms.
Oxcarbazepine and its derivatives contemplated in this invention are poorly soluble in water. Due to their poor solubility, their release from a sustained release dosage form is rather incomplete. Whereas the in vitro release of oxcarbazepine is dependent on the dissolution method, including the dissolution media used, it has been found through in silico modeling that the release of oxcarbazepine in vivo from a traditional sustained-release dosage form is relatively low. This results in reduced bioavailability of the drug making the dosage form ineffective in providing a therapeutically effective concentration in the body. This poses a serious challenge to the successful development of sustained-release dosage forms for oxcarbazepine and its derivatives.
The rate of drug release from a dosage form has a significant impact on the therapeutic usefulness of the drug and its side effects. Hence, drug release profiles must be customized to meet the therapeutic needs of the patient. An example of a customized release profile is one that exhibits a sigmoidal release pattern, characterized by an initial slow release followed by fast release which is then followed by slow release until all of the drug has been released from the dosage form.
Sustained-release dosage forms for oxcarbazepine and derivatives have been described in the art. For example, Katzhendler et al. (U.S. Pat. No. 6,296,873) describes sustained-release delivery systems for carbamazepine and its derivatives. Katzhendler et al. teaches that a zero-order release profile is achieved for carbamazepine and derivatives through the use of hydrophilic and hydrophobic polymers. Zero-order (constant) release was achieved using high molecular weight hydroxypropyl methyl cellulose (HPMC) along with some optional hydrophobic excipients. A similar approach is taught by Shah et al. (US Patent Application 20020169145). Franke et al. (US Patent Application 20040142033) discloses sustained-release formulations of oxcarbazepine that are characterized by the release of 55%-85% of the drug in 15 minutes, and up to 95% in 30 minutes. According to the authors, such release profiles provide adequate sustained-release to achieve once-a-day administration of oxcarbazepine. However, the solubility and bioavailability of the drug from these enhanced preparations suitable for once-a-day administration. The prior art does not teach how to make preparations of oxcarbazepine and derivatives characterized by sigmoidal release profiles.
It is an object of this invention to provide controlled-release formulations of oxcarbazepine for once-a-day administration. The composition of this invention is administered once-a-day and yet meets the therapeutic need of the patient. It is another object of this invention to improve the bioavailability of oxcarbazepine and derivatives thereof. It is yet another object of this invention to meet the therapeutic need of the patient without causing "spikes" in blood drug concentration that may lead to toxicity. It is yet another object of this invention to keep the blood concentration of the drug within the therapeutic window. It is yet another object of this invention to minimize the fluctuation between the Cmax and Cmin that is typical of many immediate-release and sustained-release preparations.
Many, if not all, of these objectives may be achieved in this invention through formulations that comprise both solubility-enhancing agents and release-promoting agents, and are characterized by release profiles that meet the requirement for once-a-day administration. The objectives may also be achieved through the combination of a multiplicity of units with different release profiles in one dosage unit. Minipellets/granules/tablets, which can be mixed in a certain ratio, provide a dosage form that meets the above stated therapeutic objectives.
This invention also pertains to multi-layer tablets. Multi-layer tablets can be prepared with each layer releasing the drug at a rate that is different from the rate of release from another layer. In multi-layer tablets, each layer may or may not be coated.
All of the advantages that stem from once-daily administration of a drug apply to the compositions of this invention. Some of the specific advantages of this invention may be: reduced fluctuation between Cmax and Cmin during the course of treatment and hence better therapeutic profile, reduced side-effects, improved patient compliance, and improved bioavailability of the drug.
It is the object of this invention to provide controlled-release oxcarbazepine formulations suitable for once-a-day administration. It is an additional object of the invention to incorporate a combination of solubility-enhancing excipients and/or release-promoting agents into the formulations to enhance the bioavailability of oxcarbazepine and its derivatives. Such compositions are referred to as enhanced formulations.
Oxcarbazepine was formulated to provide release profiles characterized by slow release initially, followed by rapid release and then followed by another period of slow release. Such a release profile is known to those skilled in the art as sigmoidal. Oxcarbazepine formulations with sigmoidal release profiles were tested in human pharmacokinetic (PK) studies. Based on the human data, improvements were made to the formulations by incorporating solubility enhancers and/or release-promoting excipients (such formulation are referred to as enhanced formulations). The enhanced formulations were tested in canine models and were surprisingly found to provide significant increase in bioavailability of oxcarbazepine compared to formulations containing no solubility/release enhancing excipients.
The incorporation of solubility enhancing agents in formulations containing poorly soluble drugs such as oxcarbazepine has a profound effect on the in vivo solubility and hence bioavailability of the drugs. Enhancing the solubility of oxcarbazepine results in an increase in its bioavailability and hence in better therapeutic performance of the drug. A combination of solubility and release promoters is contemplated in this invention. Preferable release promoting agents are pH dependent polymers, also known as enteric polymers. These materials are well known to those skilled in the art and exhibit pH dependent solubility such that they dissolve at pH values higher than about 4.0, while remaining insoluble at pH values lower than 4.0. Solubilizers function by increasing the aqueous solubility of a poorly soluble drug. When a formulation containing both the enteric polymer and solubilizer is exposed to an aqueous media of pH higher than 4.0, the enteric polymer dissolves rapidly leaving a porous structure, resulting in increased contact surface between the aqueous medium and the poorly soluble drug. This increased surface area enhances the efficiency of the solubilizer(s), and hence, the overall solubility and release rate of the drug is enhanced to a point where it impacts the availability of the drug for systemic absorption in patients.
Excipients that function as solubility enhancers can be ionic and non-ionic surfactants, complexing agents, hydrophilic polymers, pH modifiers, such as acidifying agents and alkalinizing agents, as well as molecules that increase the solubility of poorly soluble drug through molecular entrapment. Several solubility enhancers can be utilized simultaneously. All enteric polymers that remain intact at pH value lower than about 4.0 and dissolve at pH values higher than 4.0, preferably higher than 5.0, most preferably about 6.0, are considered useful as release-promoting agents for this invention.
Suitable pH-sensitive enteric polymers include cellulose acetate phthalate, cellulose acetate succinate, methylcellulose phthalate, ethylhydroxycellulose phthalate, polyvinylacetate phthalate, polyvinylbutyrate acetate, vinyl acetate-maleic anhydride copolymer, styrene-maleic monoester copolymer, methyl acrylate-methacrylic acid copolymer, methacrylate-methacrylic acid-octyl acrylate copolymer, etc. These may be used either alone or in combination, or together with the polymers other than those mentioned above. Preferred enteric polymers are the pharmaceutically acceptable methacrylic acid copolymers. These copolymers are anionic polymers based on methacrylic acid and methyl methacrylate and, preferably, have a mean molecular weight of about 135000. A ratio of free carboxyl groups to methyl-esterified carboxyl groups in these copolymers may range, for example, from 1:1 to 1:3, e.g. around 1:1 or 1:2. Such polymers are sold under the trade name Eudragit™ such as the Eudragit L series e.g. Eudragit L 12.5™, Eudragit L 12.5P™, Eudragit L100™, Eudragit L 100-55™, Eudragit L-30D™, Eudragit L-30 D-55™, the Eudragit S™ series e.g. Eudragit S 12.5™, Eudragit S 12.5P™, Eudragit S100™. The release promoters are not limited to pH dependent polymers. Other hydrophilic molecules that dissolve rapidly and leach out of the dosage form quickly leaving a porous structure can be also be used for the same purpose.
The release-promoting agent can be incorporated in an amount from 10% to 90%, preferably from 20% to 80% and most preferably from 30% to 70% by weight of the dosage unit. The agent can be incorporated into the formulation either prior to or after granulation. The release-promoting agent can be added into the formulation either as a dry material, or it can be dispersed or dissolved in an appropriate solvent, and dispersed during granulation.
Solubilizers preferred in this invention include surface active agents such as sodium docusate, sodium lauryl sulfate, sodium stearyl fumarate, Tweens� and Spans (PEO modified sorbitan monoesters and fatty acid sorbitan esters), poly(ethylene oxide)-polypropylene oxide-poly(ethylene oxide) block copolymers (aka Pluronics™); complexing agents such as low molecular weight polyvinyl pyrrolidone and low molecular weight hydroxypropyl methyl cellulose; molecules that aid solubility by molecular entrapment such as cyclodextrins, and pH modifying agents, including acidifying agents such as citric acid, fumaric acid, tartaric acid, and hydrochloric acid; and alkalizing agents such as meglumine and sodium hydroxide.
Solubilizing agents typically constitute from 1% to 80% by weight, preferably from 1% to 60%, more preferably from 1% to 50%, of the dosage form and can be incorporated in a variety of ways. They can be incorporated in the formulation prior to granulation in dry or wet form. They can also be added to the formulation after the rest of the materials are granulated or otherwise processed. During granulation, solubilizers can be sprayed as solutions with or without a binder.
This invention also contemplates controlled-release formulations comprising oxcarbazepine that release the drug at variable rates in the GI tract. It is also an object of this invention to design a drug delivery system to deliver drug at a very low rate early, followed by a relatively increased rate. It is another object of this invention to provide a drug release profile that is characterized by an immediate-release followed by a modified-release, such as extended-release (XR) or delayed-release (DR). These types of release profiles ensure that the Cmax (maximum concentration of the drug in blood/plasma) is kept within the therapeutic window while extending the maintenance of an effective drug level in the body. The goal of this invention is to develop a controlled-release pharmaceutical composition of oxcarbazepine that provides steady-state blood levels of MHD, an active metabolite of oxcarbazepine, at a concentration of about 2 μg/ml to about 10 μg/ml. In the preferred embodiment, steady-state blood Cmax levels of MHD fall in the range of about 6 μg/ml to about 10 μg/ml, and Cmin levels of MHD fall in the range of about 2 μg/ml to about 5 μg/ml. Reduced fluctuation between Cmax and Cmin during the course of treatment results in a better therapeutic profile, reduced side-effects, improved patient compliance, and improved bioavailability of the drug.
The desired drug release pattern contemplated by this invention is achieved by using "matrix" polymers that hydrate and swell in aqueous media, such as biological fluids. As these polymers swell, they form a homogenous matrix structure that maintains its shape during drug release and serves as a carrier for the drug, solubility enhancers and/or release promoters. The initial matrix polymer hydration phase results in slow-release of the drug (lag phase). Once the polymer is fully hydrated and swollen, the porosity of the matrix increases due to the leaching out of the pH-dependent release promoters, and drug is released at a faster rate. The rate of the drug release then becomes constant, and is a function of drug diffusion through the hydrated polymer gel.
Thus, the release vs. time curve is characterized by at least two slopes: one slope for the lag phase where drug release rate is low and a second slope where drug release is faster. The slope of the rising part of the release vs. time curve can be customized as to match the rate at which the drug is eliminated from the body. A desired release profile can be achieved by using swellable polymers alone or in combination with binders, such as gelling and/or network forming polymers.
The water-swellable, matrix forming polymers useful in the present invention are selected from a group comprising cellulosic polymers, such as hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), hydroxyethylcellulose (HEC), methylcellulose (MC), powdered cellulose such as microcrystalline cellulose, cellulose acetate, sodium carboxymethylcellulose, calcium salt of carboxymethylcellulose, and ethylcellulose; alginates, gums such as guar and xanthan gums; cross-linked polyacrylic acid derivatives such as Carbomers (aka Carbopol™) available in various molecular weight grades from Noveon Inc. (Cinncinatti, Ohio); carageenan; polyvinyl pyrrolidone and its derivatives such as crospovidone; polyethylene oxides; and polyvinyl alcohol. Preferred swellable polymers are the cellulosic compounds, HPMC being the most preferred.
The swellable polymer can be incorporated in the formulation in proportion from 1% to 50% by weight, preferably from 5% to 40% by weight, most preferably from 5% to 20% by weight. The swellable polymers and binders may be incorporated in the formulation either prior to or after granulation. The polymers can also be dispersed in organic solvents or hydro-alcohols and sprayed during granulation.
It is yet another aspect of this invention to prepare formulations of oxcarbazepine that combine multiple modified-release "units," each "unit" prepared according to any one or more of the above-disclosed dosage forms, to provide for a customized release profile.
The modified-release units comprise minipellets/granules/tablets etc., each with unique release profiles, that can be mixed in a certain ratio to provide a dosage form that meets the above-stated therapeutic objectives. Alternatively, multiple modified release units may be formed into of multi-layer tablets. Multi-layer tablets can be prepared with each layer releasing the active compound at a rate that is different from the rate of release of the active ingredient from another layer. In multi-layer tablets, each layer may optionally be coated with controlled-release polymer(s). The combination dosage forms can exhibit release profiles that comprise any/all possible combinations of immediate release (IR), delayed release (DR), and extended release (XR) formulations. Pellets/granules/tablets or each layer of a single tablet may optionally be coated.
Various hydrophobic excipients can be used to modify the hydration rate of the dosage unit when exposed to water or aqueous media. These excipients retard the wetting of the dosage unit and hence modify the release of the active agent. Hydrophobic excipients suitable for this invention are represented by, but not limited to, glyceryl monstearate, mixtures of glyceryl monostearate and glyceryl monopalmitate (Myvaplex, Eastman Fine Chemical Company), glycerylmonooleate, a mixture of mono, di and tri-glycerides (ATMUL 84S), glycerylmonolaurate, glyceryl behenate, paraffin, white wax, long chain carboxylic acids, long chain carboxylic acid esters and long chain carboxylic acid alcohols.
Examples of saturated straight chain acids, useful with the invention, are n-dodecanoic acid, n-tetradecanoic acid, n-hexadecanoic acid, caproic acid, caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, arachidic acid, behenic acid, montanic acid and melissic acid. Also useful are unsaturated monoolefinic straight chain monocarboxylic acids. Examples of these are oleic acid, gadoleic acid and erucic acid. Also useful are unsaturated (polyolefinic) straight chain monocarboxylic acids such as linoleic acid, linolenic acid, arachidonic acid and behenolic acid. Useful branched acids include, for example, diacetyl tartaric acid.
Examples of long chain carboxylic acid esters include, but are not limited to: glyceryl monostearates; glyceryl monopalmitates; mixtures of glyceryl monostearate and glyceryl monopalmitate (Myvaplex 600, Eastman Fine Chemical Company); glyceryl monolinoleate; glyceryl monooleate; mixtures of glyceryl monopalmitate, glyceryl monostearate, glyceryl monooleate and glyceryl monolinoleate (Myverol 18-92, Eastman Fine Chemical Company); glyceryl monolinoleate; glyceryl monogadoleate; mixtures of glyceryl monopalmitate, glyceryl monostearate, glyceryl monooleate, glyceryl monolinoleate, glyceryl monolinoleate and glyceryl monogadoleate (Myverol 18-99, Eastman Fine Chemical Company); acetylated glycerides such as distilled acetylated monoglycerides (Myvacet 5-07, 7-07 and 9-45, Eastman Fine Chemical Company); mixtures of propylene glycol monoesters, distilled monoglycerides, sodium stearoyl lactylate and silicon dioxide (Myvatex TL, Eastman Fine Chemical Company); mixtures of propylene glycol monoesters, distilled monoglycerides, sodium stearoyl lactylate and silicon dioxide (Myvatex TL, Eastman Fine Chemical Company), d-alpha tocopherol polyethylene glycol 1000 succinate (Vitamin E TPGS, Eastman Chemical Company); mixtures of mono- and diglyceride esters such as Atmul (Humko Chemical Division of Witco Chemical); calcium stearoyl lactylate; ethoxylated mono- and di-glycerides; lactated mono- and di-glycerides; lactylate carboxylic acid ester of glycerol and propylene glycol; lactylic esters of long chain carboxylic acids; polyglycerol esters of long chain carboxylic acids, propylene glycol mono- and di-esters of long chain carboxylic acids; sodium stearoyl lactylate; sorbitan monostearate; sorbitan monobleate; other sorbitan esters of long chain carboxylic acids; succinylated monoglycerides; stearyl monoglyceryl citrate; stearyl heptanoate; cetyl esters of waxes; cetearyl octanoate; C10-C30 cholesterol/lavosterol esters; and sucrose long chain carboxylic acid esters. In addition, waxes can be useful alone or preferably in combination with the materials listed above. Examples of these are white wax, paraffin and carnauba wax.
Drug, polymers, and other excipients are typically combined and wet granulated using a granulating fluid. However, other methods of forming granules such as slugging, and roller compaction can also be used to manufacture matrix granules. Matrix tablets can also be made by direct compression. In wet granulation, typical granulating fluids are: water, a mixture of water and alcohol, anhydrous alcohol. Wet granules can be made in any granulating device such as mixers, high shear granulators, and fluid bed granulators. Granules can be dried in appropriate drying equipment such as fluid bed dryers, ovens, microwave dryers etc. Granules can also be air-dried. Dried granules can be milled using appropriate milling device to achieve a particular particle size distribution. Granules can be filled in to capsules, or blended with other excipients and tableted on a tablet press. Granules can also be packaged into sachets for sprinkle application. Other excipients used to aid tableting are well known to those skilled in the art and include magnesium stearate, talc, cabosil etc. Granules and tablets can, optionally, be coated to further modify release rates. Furthermore, formulations can also optionally contain dyes.
Optionally, but preferably, the tablet composition can contain one or more lubricants, which may be added to assure proper tableting. Non-limiting examples of lubricants include magnesium stearate, calcium stearate, zinc stearate, stearic acid, polyethylene glycol, leucine, glyceryl behenate, sodium stearyl fumarate, hydrogenated vegetable oils, and other waxes, including but not limited to, beeswax, carnuba wax, cetyl alcohol, glyceryl stearate, glyceryl palmitate, and stearyl alcohol. The lubricant, when present, is typically included in an amount of from about 0.1 wt. % to about 20 wt. % of the composition, preferably from about 1 to about 10 wt. %, and more preferably about 0.3 to about 3.0 wt. %.
The oxcarbazepine dosage can be formulated into tablets, granules, and pellets. The steps involved in the manufacturing of these dosage forms are well known to those skilled in the art. Briefly, tablets can be compressed from directly compressible blend containing the active or pre-formed granules. The tablets can be coated or not coated. The coating may optionally impart modification of release. Granules can be made by high shear granulation or fluid bed processing. The granules may or may not be coated. Pellets can be manufactured by drug layering on inert carriers such as sugar spheres. Pellets can also be manufactured by extrusion/spheronization process. The pellets may or may not be coated. Coated pellets and granules can be filled into capsules.
Formulations of this invention can also be made in pelletized forms, which can be filled into capsules or dispensed in sachets for sprinkle application. Each pellet is composed of the drug, swellable polymer(s) and other excipients that aid the processing. Pellets can be prepared in one of the many ways that are known by those skilled in the art. These include, for example, extrusion/spheronization and roller compaction (slugging). In the extrusion/spheronization technique, drug is mixed with swellable polymer(s), such as cellulosic polymers and other excipients. The blend is then granulated in a high shear granulator. The wet mass is then passed through an extruder and spheronized using a spheronizer. The pellets are then dried in an oven or fluid bed processor. The dried pellets are either processed further or encapsulated without further processing.
Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting.
The invention now will be described in particularity with the following illustrative examples; however, the scope of the present invention is not intended to be, and shall not be, limited to the exemplified embodiments below.
Table 1 provides the formula composition of oxcarbazepine controlled-release preparations with sigmoidal release profiles. Granules were prepared by high shear granulation using anhydrous ethanol as the granulating liquid. All ingredients, except for magnesium stearate, were charged in to VG-65/10M high shear granulator. The dry powders are blended by running the blade for 3 minutes, after which time the anhydrous ethanol was sprayed onto the mixing blend at a spray rate of approximately 40-60 gm/min. After about a minute of spray, the chopper on the VG-65/10M was started and run throughout the spray. Once the granulation was completed, the granulation was discharged from the VG high shear granulator, spread on an appropriate tray and placed in an oven to dry at 40� C. for 24 Hrs. Alternatively, granules can be dried using a fluid bed processor. Dry granules were screened through an 18-mesh screen. Screened granules were blended with magnesium stearate in a proportion of 99.5% granules and 0.5% magnesium stearate. The blend was then tableted on a rotary tablet press.
The three formulations from the Example 1 were evaluated in humans to obtain pharmacokinetic information. An immediate release tablet (Trileptal� 600 mg) was used as a control reference. The formulations were examined in a randomized, single dose, crossover study in healthy human volunteers. Blood samples were analyzed for both the parent molecule oxcarbazepine and its metabolite (the monohydroxy derivative, MHD).
Table 2 provides the mean PK parameters for MHD. The PK profiles are shown in
The solubility of oxcarbazepine in the presence of excipients was evaluated as follows:
Excipients were dissolved in phosphate buffer to make solutions with concentrations shown in Table 3. One gram of oxcarbazepine was then mixed with 19 gm of the excipient solution. The mixture was rocked overnight at room temperature and then filtered using 0.22 μm filter. The filtrates were analyzed by HPLC. The solubility results are given in Table 3 and
Tables 4 and 5 provide the composition of the formulation containing solubility- and release-enhancing agents. Granules were manufactured by high shear granulation using water as the granulating liquid. All ingredients, except for magnesium stearate, were charged into a VG-65/10M high shear granulator. The dry powders were blended by running the blade for 3 minutes, upon which time water was sprayed onto the mixing blend at a spray rate of approximately 40-60 gm/min. After about a minute of spray, the chopper on the VG-65/10M was started and run throughout the spray. Once the granulation was completed, the granulation was discharged from the VG high shear granulator, spread on an appropriate tray and placed in an oven to dry at 40� C. for 24 Hrs. Alternatively, granules can be dried using a fluid bed processor. Dry granules are screened through an 18-mesh screen. Screened granules were blended with magnesium stearate in a proportion of 99.5% granules and 0.5% magnesium stearate. The resulting blend was then tableted on a rotary tablet press. Dissolution profiles for these formulations are shown in
Six male beagle dogs were dosed orally with the formulations in the order given in Table 6. Blood was drawn over a 24 Hr period and blood samples were analyzed by HPLC. A noncompartmental analysis of the data was used to generate Tmax, Cmax, AUClast, and AUCinf. Relative Bioavailability was calculated in Excel using the AUClast and AUCinf for the CRf formulation as the control. The PK profiles for oxcarbazepine and 10-hydroxycarbazepine are given in
In silico modeling was carried out for various hypothetical systems. Results are shown in
The three solubility enhanced prototypes from the Example 4 were evaluated in humans to obtain pharmacokinetic information. An immediate release tablet (Trileptal� 300 mg) given BID was used as a reference. The formulations were examined in a randomized, single dose, crossover study in healthy human volunteers. Blood samples were analyzed for both the parent molecule oxcarbazepine and its metabolite (the monohydroxy derivative, MHD).
Table 8 provides the mean PK parameters for MHD. The PK profiles are shown in
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MILAN — Gianfranco Ferré is on a mission: transforming a high-end ready-to-wear line into a high-profile, international brand.
That's the goal that Enrico Mambelli has set out to accomplish since he joined the fashion house in June as chief executive officer, after holding key posts at Nike Italy, GFT and Cerruti Group.
In an exclusive joint interview, Mambelli and Ferré outlined the company's global strategies, which they orchestrated together.
So far, the marriage between IT Holding, the Italian clothing manufacturer, and Ferré, consummated in December 2000, seems to be working out.
"I'm happy. I feel inspired and motivated because I've kept my independence and we're working for a joint goal: to grow the brand," said Ferré, trim and lean after having shed more than 65 pounds. Reports in Milan fashion circles had it that Ferré's diet was the consequence of a minor stroke suffered last spring, but a company spokeswoman firmly denied that.
In 2001, Gianfranco Ferré wholesale volume was $226.8 million, with a revenue stream derived from royalties of $19.7 million.
Tonino Perna, IT Holding's chairman and ceo, said he's content with the results scored thus far. "By the end of the year, our first goal to create a joint project developed by a team of managers together with Mr. Ferré, will have been reached," Perna said.
Among the key points on the company's agenda:
l Retooling the firm's structure to bring in-house all of its divisions — the brand's positioning, the supervision of the retail network, the communications and marketing departments and control over licenses.
l An aggressive retail rollout and a new store concept that includes a beauty spa.
l Boosting the accessories division and launching a gold jewelry line in the spring.
l Streamlining existing lines and revising the portfolio of licensees.
l Opening new showrooms or signing public relations agencies in strategic locations, including Los Angeles, to tap into the movie star system.
l Creating new posts to bolster the executive team with managers that will act as watchdogs over the brand.
All this coincides with two seasons of strong Ferré' collections, where the designer tempered his signature over-the-top drama and glamour by using a cleaner and more contemporary hand.
"My approach to the collections has changed because I wanted to steer away from clothes that were too couture-oriented. My focus is on basic and separate pieces that are interchangeable, complemented with stronger seasonal pieces," Ferré said. "That's the direction the world is moving in and I'm going along."
This philosophy has enabled the designer to keep a lid on prices.
During Milan fashion week in October, Patricia Fields, the stylist for "Sex and the City," swung by Ferré's showroom and picked out about 20 looks from spring's sophisticated collection that embraced two of the season's top trends: the sportif movement and the Asian motif.
The changes afoot at the licensing contracts are numerous. As reported, Ferré plans to discontinue the Gieffeffe, Gianfranco Ferré Studio, Jeans and Forma lines next year when the licensing agreement with Marzotto expires.
At the same time, it will also amicably end its 20-year relationship with De Silva for fragrances and body lotion. Starting in January, ITF, IT Holding's fragrance division, will get to work on a new women's fragrance, slated to bow next year.
And rather than an overdose of lines, Ferré plans to regroup its existing labels into two collections: a top-tier Gianfranco Ferré line that includes the ready-to-wear and Forma, and Ferré, a line aimed at a younger crowd that will include the jeans and Gieffeffe.
"From Ferré, the consumer wants extreme quality, details, and distinction," Ferré said.
IT Holding, which also owns Romeo Gigli, Malo, Gentryportofino and Exté, boasts a vertical structure articulated in various divisions: ITC for the production of top-drawer apparel lines; eyewear manufacturer Allison; the ITF perfume division; PAF for accessories, and Ittierre, which churns out jeans lines, including Versus and D&G.
Mambelli and Ferré are eager to exploit the synergies and resources of this setup.
"On one hand, we're bringing in-house the various divisions to have more control over image and quality," Mambelli said. "On the other, the industrial side will be controlled by IT Holding."
The retail expansion and the new store concept also represent a big leap in raising brand awareness.
"Architecture is my background I wanted to emphasize quality, a more accessible luxury for every day and in the products carried in the various areas," Ferré said.
From a technical standpoint, the project was supported by Gabellini & Associates, the New-York based interior design studio.
The project, which will be carried out through 2004, comprises the opening or refurbishing of a string of new generation stores, starting with Paris in January and Capri next spring.
To inaugurate the new boutique in Paris, the designer will stage a small runway show spotlighting key looks from spring for his longstanding clients. It will be held at the Jeu de Paume museum on Jan. 21.
Also next year, the existing Ferré stores here and in Cannes, Porto Cervo and New York will be restyled according to the new model, while eight new franchised boutiques will open at all latitudes, from Seoul to St. Petersburg and Shanghai to Athens.
Mambelli quantified the company's retail investment as about $2.5 million for every store that measures an average of 5,400 square feet.
Starting next spring, clients shopping at the newly refurbished store here will be in for a surprise: an adjacent, 2,160-square-foot spa, the fruit of an agreement between Ferré and Espa, a leading British spa company.
Clients can unwind with a two-hour relaxation session that includes a massage, a steam bath, and a dip in the vitality pool or special mud treatments.
"This project is strategic because our client comes in to buy an emotion, whether it's a massage or a dress. We want to offer a service and get the consumer more involved in the Ferré world," Mambelli explained.
For the occasion, Ferré will develop a full line of towels, terrycloth robes and beauty creams.
Structurally, the blueprint for the stores resembles that of a home and its many rooms, decorated with different elements, at times in harmony and at others in contrasts, to house the full array of products.
"This is a young company but it still has 25 years of history," Ferré said. "This new store concept was the most logical and appropriate way to express the product range."
Yellow Tunisian marble floors contrast with lacquer red shantung silk panels while fixtures and tables in light honey briarwood are juxtaposed against darker brown rosewood tones.
Decorative elements include crystal chandeliers, mother-of-pearl mosaic trays, stuccoed details and silver ornaments.
Ferré plans to update the display of the merchandise, normally styled around a theme, every few weeks to keep the store presentation lively.
About 30 percent of the stores' space will be dedicated to accessories, which will greet customers as they walk in.
"This entryway of accessories is strategic because it allows customers to enter the Ferré world more frequently," Mambelli said. "It's easier to buy a scarf or a fragrance than a dress."
Mambelli is channeling resources and energies to boost Ferré's accessories division, which also includes footwear as well as small objects for the home, to ultimately increase its share of total sales from today's 5 percent to between 20 and 25 percent over the next year to 18 months.
"Quality materials are fundamental for the accessories," Ferré said, "with a range from crocodile to goatskin colored with vegetable dyes that give it a natural structure without extra support."


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1999 GMC Yukon Denali Q&A
1999 GMC Yukon Denali Question: stuck in 4 wheel
it is stuck in 4 wheel high, how do i diagnos this problem? - Smart1
6 Answers
Answer 2
Had the same issue while in the OBX. Ended up being the last thing I checked working from the top down. Check the plug connection on the tranfer case. Mine came unplugged and the transfer case was not getting the signal from the computer to change. No fault codes were stored. - ssperlik
Answer 4
i have the same truck with the same problem. the plug on the drivers side of the transmission over crossmember came loose and some pins were green from water getting in there. if thats your problem get some small brushes and take your time cleaning them. dont bend any pins spray with contack cleaner and blow dry. it worked for me - Visitor
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text:
QuaternionKeyFrameCollection.IList.Add Method
.NET Framework 4.6 and 4.5
Adds an item to the IList.
Namespace: System.Windows.Media.Animation
Assembly: PresentationCore (in PresentationCore.dll)
'Declaration Private Function Add ( _ keyFrame As Object _ ) As Integer Implements IList.Add
- keyFrame
- Type: System.Object
The object to add to the IList.
Return ValueType: System.Int32
The position into which the new element was inserted, or -1 to indicate that the item was not inserted into the collection.


text:
Failing Taunton (MA) Dam Built In 1832
"It could go on for days," said Mayor Robert Nunes of the crisis that had forced the indefinite evacuation of a nearly 3-square mile area of this sprawling, working- class city.
Just north of downtown, the Whittenton Pond Dam's safety rails warped, part of its rotted wooden foundation strained, one of its water gates failed, and the resulting vibrations from all this threatened yesterday to overwhelm it, said authorities.
But by late yesterday, the pre-Civil War era dam was still standing, and the water levels of the lake that feeds the rain-swollen Mill River had dropped several inches, said state officials.
"Essentially what you've got is an old structure that was poorly maintained, which is essentially suffering from fatigue," said Michael Misslin, deputy commissioner of the state Department of Conservation and Recreation. "Struc tures that are prone to weakness reveal themselves at the worst possible times."
This week's crisis was not Taunton's first brush with flooding and potential dam failures.
Charles Crowley, a local historian and member of the Taunton City Council for the past 18 years, said the dam was built in 1832 and last underwent a significant renovation in 1959.
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Confident and explains condition well. Courteous as well
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Dr. Alton is the best doctor and a skilled surgeon. He explains everything, has time for questions and is genuine.
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Michael Franti & Spearhead
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I admit to having the hardest time writing lately. What with the book release in a few days, my plate has brimmed to overflow; guest posts and radio interviews and magazine articles taunt me like heaps of ice cream scoop-shaped mashed potatoes on my cafeteria tray. I literally have about five half-written articles staring at (read more…)
Routine isn't a dirty word
As you start this week, don't forget the cousin to just-do-the-thing-in-front-of-you. It's called The Routine. Some people love them, some people hate them. Me? I'm somewhere in the middle. There are times when the thought of routine gives me hives, because I do thrive on change and new situations. I see the adventure in the (read more…)
One bite at a time together: Get help (project 51)
I'm still slowly working my way through Tsh's ebook One Bite at a Time and journaling my progress here. My favorite part of the book is that it can be done in any order, which is helpful for my oftentimes scattered brain. Somehow there is so much mama guilt out there. Or rather, in here. (read more…)
Question for you (no, really!): How are you currently simplifying?
While I was gone the past few weeks, Kyle got down to work here at home. I'd get occasional texts from him like, "Can I get rid of your teacup with the broken handle?" or "I'm getting rid of more clothes—hooray!" One time when we talked, he told me he had a surprise for me—he (read more…)
May we all be Mexican fishermen
As you start this week, may you find contentment in the pursuit of enough. With money, time, relationships, your home, and even your dreams and goals, may you peacefully and boldly pursue that sweet spot called enough, where you aren't in need, but also aren't burdened with needless abundance. And in this process, may you (read more…)


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Flamenco Communication
A Specialized Interactive Workshop, created by Temo (for Dancers, Guitarists, and Singers) on what is required from each of them to effectively communicate and interact with one another through a breakdown on the structure of flamenco dance and song forms. Click here for more info on Flamenco Communication.
Location: Studio Ritmo Flamenco, 1212 Evergreen Avenue, Naperville, IL 60540
Palos: Sevillanas Mini Workshops (All Levels)
Date: Sat., Feb. 7, 2015
Time: 9:30- 10:30a.m
Fee: $55 Read More »


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Shanghai, Shanghai Municipality, China
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Live. Love. Be free.
Her I am: Taking life as it comes! Waiting for the right moment, things to slide into place;)...anyone, wana do something? Can YOU inspire me? entrall me?...
How mixed IS the world?
Try and get some connection, something with meaning, sometimes I upset people, sometimes they do to me!
Donie in Southie
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Bullet, Asheville
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Jack Hurt, Merritt Island (...)
Susan, Indialantic, Meltbourne beach
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Adrien picking me up outside Annemasse, or helping Anna off the bus in Malmo and chatting Malvin on the beach in Skanor is couch surfing then that's my experience.
Oh yeah, Laurant gave me a drink and a hat near Montelimar.
The Patch Adams 'hospital' near Hillsboro, Westie (WV)
Marcie and her truck, five days, from John Hanson Highway 50 'on ramp' at Garden City Drive, near New Carrolton, Washington D.C - Rehobeth Beach, Delaware (including, Georgetown, DL, Prince George, VA, Sunbury, PA, Strasurg, MD, A Wonderful nightime tour of Residential Washington, D.C, Dayton, NJ)
Two weeks in Miami with a woman whom I can't remember the name of right now (Roll over Batehoven's playing' things can't be bad - they are I'm at home with the 'rents)
Junghee in Austin, TX - lovely time
Slept in a state park in Maryland
Christina picked me up near Crescent beach, two nights at her boyfriend Marks place, one night in Gaineville and a ride to Titusville (what a chick)
Cocoa Beach bar - one night
Jetty Park RV campsire, Cape Canaveral - one night
Angela, 405 gas station, her house Titusville for one night
Joel and Jay, the Miami brothers, Port St John for a week (great lads)
Judy gave me ten bucks at Vero Beach - (Cheers luv)
Night roaming Fort Pierces strip mall district
Cecil, Fort Pierce
Night tenting in a condo complex in Key West, rumbled in morning but a good nights kip, a gracious to the gent whom informed me he'd call the police in five minutes if I didn't get up!
John, Big Coppit, Key West
This hostel in Florida shity, I mean city! Honestly, it is a city, it's shit too, though;)
Tim, Fort Pierce, FL
Stressed Eric and his woman
Dallas/Fort Worth Airport - thanks Charlene, you were very kind
Aircraft back to the U.l, U.S airways had shit cabin crew.
Eddie and Junghee - amaing people, Austin.
Good food.
Better company;)...
Nice music:)
yes and (you guessed it...)
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Survived death in Idaho on a winters night February 2008.
Salt Lake City Marathon
London-Amsterdam cycle
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Hitching to Britains furthest southern, western, northern and eastern points.
Hitch hiking w. female trucker out of DC, up and around NE USA, finishing back at our first nights stop,ah!)
Skipping train to south of France and back.
Hitch hiking around Ireland (Republic and Northern).
Skipping train from Oslo - London.
Hitch hiking to Belgium, Luxembourg, France and back.
Skipping train to Sicilia, AND BACK! 1st lcass lovely food;)
Vietnam (with yi)
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Dakshin Haryana Bijli Vitran Nigam - DHBVN-Faridabad (Electricity)
41 Reviews
deepak doomra
Dear Sir/Madam,
Sector-19 in Faridabad suffers unpredicted cuts and outages every summer. Yesterday evening (20 May 09) their was an outage at 21:30 hrs which could be restored temporarily today at 09:45 AM (outage lasting for almost 12 hours) in extreme summer. It again went off at 11:30 AM and has not returned till the time of writing this complaint. Their is no redressal to our problems and a sector has been converted worse than a slum.
This is routine every summers and DHBVNL have not upgraded their distribution netwroks and transformers. Its pathetic and your intervention will make them accountable.
Thansk & Regards/
Deepak Doomra
|40 Comments Updated:
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1989 - 2015
Derek D. Huelsenbeck AGE: 26 • Wharton Derek D. Huelsenbeck died on Tuesday, June 30, 2015 at Compassionate Care Hospice at St. Clare's Hospital/Dover. He was 26. Born in Denville, he lived in Rockaway Borough...
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Mary M. David
1943 - 2015
Mary M. David AGE: 71 • Rockaway Twp. Mary M. David died on Sunday, May 3, 2015 at St. Clare's Hospital/Denville. She was 71. Born in Scranton, PA to the late William and Mary Sholler, she was raised in Clarks...
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Published in Daily Record on May 5, 2015
1919 - 2015
Joseph A. Grow WWII pilot on bombing missions over Europe, Reaction Motors engineer on X-15 in his native Rockaway, 95 Joseph A. Grow, 95, died on Tuesday, April 28, 2015, at home, surrounded by his family who loved him...
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Published in Star-Ledger on Apr. 29, 2015
Joseph A. Grow
1919 - 2015
Joseph A Grow AGE: 95 • Rockaway Borough Joseph A. Grow, 95, died on Tuesday, April 28, 2015 at home surrounded by his family who loved him dearly. Born and raised in Rockaway, NJ, Joseph graduated from Rockaway...
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Published in Daily Record on Apr. 29, 2015
Ruth E. Murphy
1926 - 2015
Ruth E. Murphy AGE: 88 • Rockaway Ruth E. Murphy died peacefully on Wednesday, April 22, 2015 surrounded by her family. She was 88. Born and raised in Newark, she graduated from St. Vincent's Academy in Newark...
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Published in Daily Record on Apr. 24, 2015
Roy Ball Jr.
Roy Ball, Jr. AGE: 83 • Rockaway Borough Roy Ball, Jr. died on Tuesday, March 31, 2015 at Morris View Healthcare Center. Born and raised in West Orange, he moved to Rockaway Borough in 1980. He had served in the...
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Published in Daily Record on Apr. 12, 2015
Ida C. Redmond
1927 - 2015
Ida C. Redmond AGE: 88 • Rockaway Borough Ida C. Redmond died on Saturday, April 11, 2015 at home. She was 88. Born in Roseland, she was a resident of Rockaway Borough since 1950. Mrs. Redmond was the co-owner...
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Published in Daily Record on Apr. 12, 2015
Sheryl Lynn Rodimer
Sheryl Lynn Rodimer AGE: 57 • Rockaway Boro. Sheryl Lynn Rodimer died unexpectedly on Saturday, April 4, 2015. She was 57. Born in Denville, she was a life resident of Rockaway Borough. She was a homemaker and a...
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Published in Daily Record on Apr. 7, 2015
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