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SANFORD — Doris Cameron Simpson, age 76, died Tuesday, March 26, 2013 from complications of ALS (Lou Gehrig's disease).
Mrs. Simpson was born in Lee County, daughter of the late James and Ruth McCain Cameron. She was preceded in death by half-brothers, Clarence, James, Alonzo and Nath Cameron; and half-sisters, Elizabeth Matthews and Viola Lea.
Mrs. Simpson was a 1954 graduate of Greenwood High School and King's Business College in Raleigh and retired from Civil Service as Budget Officer, Womack Army Medical Center, Ft. Bragg. She was a lifelong member of Pocket Presbyterian Church, where she served as an Elder, Clerk of Session, member of Choir and held several offices in Presbyterian Women. She was presented Honorary Life Membership in Presbyterian Women in 2003. She was a member of the Sanford Chapter of the National Active and Retired Federal Employees Association for many years. Mrs. Simpson was a member of the Sandhills Emmaus Community.
She is survived by her loving and faithful husband of 55 years, Lawrence; son, Rev. Thomas Simpson and wife Sharon of Goldston; daughter, Lynda Ward and husband Leonard of Sanford; a sister, Carol Cox and husband Boyce of Sanford; brothers, Harold Cameron and wife Rita of Aberdeen, and Joel Cameron and wife Jackie of Sanford; grandchildren, Sydney S. Karlau and husband Josh of Cary, Erin Simpson of Raleigh, and Kevin, Jeffrey and Matthew Ward of Sanford; special friend, Jerry Vuncannon; caregivers, Pauline Holland, Priscilla Goldston and Kim Purcell.
A Celebration of Life service will be held at Pocket Presbyterian Church on Saturday at 2 p.m. conducted by the Rev. David Dudley and Joel Cameron.
The family will greet friends in the church fellowship hall after the service, and at other times at the family home.
In lieu of flowers, donations may be made to Pocket Presbyterian Church Building Fund, 669 Pocket Church Rd., Sanford, N.C. 27330; The ALS Association's Jim "Catfish" Hunter Chapter, 4 N. Blount St., 2nd Floor, Raleigh, N.C. 27601; or Community Hospice, 1836 Doctors Dr., Sanford, N.C. 27330.
The family would like to thank friends for every act of kindness shown during the years since ALS diagnosis in 2006.
Online condolences may be made at www.rogerspickard.com.
Arrangements are by Rogers-Pickard Funeral Home.
Paid Obituary
SILER CITY — Josephine Louise Fields, 80, of Sam Fields Road, Siler City, died Tuesday, March 26, 2013 at Siler City Care & Rehabilitation.
Ms. Fields was born in Chatham County on February 15, 1933, the daughter of Sam John and Lillie (Braswell) Fields. She had been a secretary at Chatham Novelties, Siler City, NC and had worked at Bill's Good Food. Josephine was of the Christian faith and was preceded in death by her parents; sisters, Maggie Fields, Doris Groce and a special friend, Billy Dixon.
She is survived by nephews, Sam Groce and wife Julie, and Doug Groce; niece, Janet Groce; and great-niece, Kaylyn Groce, all of Siler City.
The family will receive friends Friday, March 29, 2013 at the home of Sam Groce, 620 Sam Fields Road, Siler City from 6-8 p.m. and other times at the home of Janet Groce, 884 Sam Fields Road. There will be a graveside memorial service on Saturday, March 30, 2013 at 11 a.m. at Chatham Memorial Park, 13260 Hwy 64 West, Siler City with Rev. Darrell Bordeaux officiating.
In lieu of flowers, memorials may be made to Chatham Child Development Center, 221 Chatham Square, Siler City, NC 27344.
Smith & Buckner Funeral Home is assisting the family.
Online condolences may be made at www.pughfuneralhome.com.
Paid Obituary
SALISBURY — Mrs. Reba Simmerson Shoaf, 90, of Salisbury, passed away Tuesday, March 26, 2013.
Born March 16, 1923 in Forsyth County, N.C. to the late Ann Owens Simmerson and Luther Bryant Simmerson, she was educated in Davidson County schools and graduated from Rowan Cabarrus Community College with a degree as an LPN. Mrs. Shoaf worked as a seamstress at Belk and retired from the VA Medical Center. She was a caregiver to many, loved gardening, and took pride in her yard.
Mrs. Shoaf was a member of Central United Methodist Church and the Morning Circle.
Preceding her in death was her husband, Hollis Wade Shoaf on August 16, 1962; two brothers, one sister and son-in-law, S.W. Brown Jr.
Surviving are her children: Rebecca "Becky" Brown of Mocksville, NC, Ann Ludwig and husband J.C. of Salisbury, NC, Nancy Thomas and husband Larry of Sanford, NC, Lynn Hulin and husband Jim of Linwood; grandchildren: Susan Hanschu of Mocksville, NC, Renee Sanders (Donnie) of Mocksville, NC, William Ludwig (Christa) of Rockwell, David Ludwig of Matthews, Jeremy Thomas (Amy) of Sanford, Leah Thomas of Raleigh, Eric Hulin (Mary) of Smithfield, NC and Laura Gorman (Neal) of Lexington, NC. Also surviving are great-grandchildren, Wesley Ludwig, Luke Thomas, Abby Thomas, Ava Hulin, Katie Gorman, Kendall Gorman, and Alston Gorman.
The funeral service will be at 2 p.m. Friday (March 29) at Central United Methodist Church, 200 4th St., Spencer, conducted by Rev. Don Mason, Minister of Central United Methodist Church and Rev. Susan Bame, Minister of Holy Cross Lutheran Church in Mocksville, NC. The family will receive friends following the funeral service. At other times the family will be at the home of Lynn Hulin. Burial will be private.
The family wishes to express the deepest appreciation to Joyce Swinson at the Hope House Assisted Living for her care of our mother and to Cyndi Frasier who made her last two months special.
In lieu of flowers, memorials may be made to Central United Methodist Church, PO Box 203, Spencer, NC 28159.
Summersett Funeral Home is serving the Shoaf family.
Online condolences may be made at www.summersettfuneralhome.com.
Paid Obituary
SANFORD — Mrs. Jeanne Mae Carroll Perdue, age 77, of Sanford, NC, died Tuesday, March 26, 2013 at Liberty Commons Retirement Center.
She was born in Lee County, NC on August 18, 1935, to the late Clyde Lewis Carroll and Bonnie Ruth Holder Carroll. In addition to her parents, she was preceded in death by a son, William David Perdue; sister, Hazel Roloff; and six brothers, Lynn, Malcolm, Melvin, Donald, Clyde Jr., and John Carroll. Mrs. Perdue was a homemaker.
She is survived by her husband, Edward William Perdue; two sons, Darryl Edmond Perdue and wife Brenda and Douglas Perdue, all of Sanford; three daughters, Sharon Hart and husband Douglas of Carrboro, Sheryl Smith and husband David of Sanford, Karen D'Angelo and husband Tony of Sanford; one brother, Boyce Carroll of Greensboro; two sisters, Shirley Calendine and Janice Baker, both of Sanford; thirteen grandchildren: Jacob Hart, Jeffrey Smith, Shannon Smith, Brooke Perdue, D.J. Perdue, Eliza Perdue, Blaine Douglas Perdue Jr., Ashley Perdue, Joshua Stanley, April Stanley, Jenny Pat, Lindsey Perdue and David Perdue; and twelve great-grandchildren.
The family will receive friends Friday, March 29, 2013 from 6:00 to 8:00 PM at Bridges-Cameron Funeral Home and the funeral will be Saturday, March 30th at 2:00 PM at Swann Station Baptist Church with Rev. Russell Blackmon presiding. Burial will follow at the McDougald-Holder Cemetery in Sanford.
Condolences may be made at www.bridgescameronfuneralhome.com.
Arrangements by Bridges-Cameron Funeral Home, Inc.
Paid Obituary
SANFORD — Davie Cooper Winstead, 86, died Wednesday (3/27/13) at Central Carolina Hospital. Arrangements are incomplete but will be announced by Bridges-Cameron Funeral Home.
Condolences may be made at www.bridgescameronfuneralhome.com.


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S&A Presents: The Dojo Open Mic (10/23/14)
Published on October 20th, 2014 | by A. Sizemore
Interactive crowd – check! New York's top undiscovered talents – check! Thursday, October 23rd is the next show for our interactive Open Mic series #TheDoJo which includes a panel format for those looking to take their performance game [&hellip... Read More →

subset: commoncrawl


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8/5/2015Titan Cafe
8/21/2015 - 8/21/2015
8/24/2015 - 8/24/2015Courtyard
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It is the intent of the Board of Trustees to ensure that the Board and the employees of the College are appropriately indemnified from liability claims. The Board directs the President to ensure that the College annually purchases insurance coverage which provides School Leaders Errors and Omissions Liability protection. The policy should provide coverage limits of at least $1,000,000 per wrongful act as well as coverage of at least $100,000 for defense attorney expenses. The coverage should be reviewed annually and policy coverage limits evaluated for appropriateness and value relative to premium renewals.
CCBC Main Campus
1 Campus Drive Monaca, PA 15061
CCBC Aviation Sciences Center125 Cessna DriveBeaver Falls, PA 15010
CCBC Washington County Center at SouthpointeBailey Center I 125 Technology Drive Canonsburg, PA 15317


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Welcome to My Fantasy Raw. Lets get the show underway.
- In Ring Segment: Raw General Manager John 'Bradshaw' Layfield calls out the WWE Champion Daniel Bryan. Bryan makes his way to the ring. JBL criticizes Bryan for getting "intentionally" disqualified last night. Bryan denies getting himself disqualified on purpose. JBL announces Daniel Bryan will defend the WWE Championship at New Years Revolution is 6 weeks in an Elimination Chamber match. Tonight, Daniel Bryan faces Kane in a No Disqualification match. If Kane wins, he qualifies for the Elimination Chamber.
- CM Punk defeated The Miz to qualify for the Elimination Chamber match (Time of contest - 09:37) Punk beats Miz after connecting with the GTS.
- Backstage Segment: The COO Triple H tells JBL he likes the Elimination Chamber match. He says he's not sure if he likes JBL's treatment of Daniel Bryan though. JBL tries defending himself but Triple H cuts him off.
- Backstage Interview: WWE Champion Daniel Bryan talks to Scott Stanford about having to face Kane in a No DQ match tonight.
- The Intellectual Americans (c) (with Zeb Colter) defeated The Money Makers (with AJ Lee) to retain the World Tag Team Championship (Time of contest - 08:54) Jack Swagger makes Drew McIntyre tap out to the Patriot Lock.
- After the match, AJ Lee enters the ring. She screams at McIntyre before slapping him across the face. Zack Ryder tries calming her down but she slaps him too. AJ leaves the ring as McIntyre and Ryder are left shocked and furious in the ring.
- Backstage Segment: Triple H congratulates CM Punk on his win earlier. Punk thanks him before quickly leaving.
- Divas Champion Natalya defeated Tamina Snuka in a non title match (Time of contest - 06:08) Natalya makes Tamina submit to the Sharpshooter.
- Backstage Interview: AJ Lee explains why she turned on The Money Makers earlier. She says she's a winner and can't hang around losers anymore.
- In Ring Segment: Paul Heyman, Roman Reigns and Intercontinental Champion Curtis Axel enter the ring. Heyman grabs a microphone. He says it wasn't any of his clients fault that Team Heyman lost at Survivor Series. Two of them will prove that right now.
- Ryback & Fandango (with Summer Rae) defeated Intercontinental Champion Curtis Axel & Roman Reigns (with Paul Heyman) (Time of contest - 09:29) Fandango wins the match for his team by pinning Axel after hitting the Diving Leg Drop from the top rope. Ryback takes out Roman Reigns outside the ring to ensure the pinfall.
- After the match, Curtis Axel and Roman Reigns argue over who's to blame for the loss. Heyman separates them. Reigns then comes storming in with a huge Spear. Heyman manages to just move out of the way and Reigns connects with Axel. Reigns leaves the ring as Heyman is left stunned.
- Backstage Segment: Triple H enters Daniel Bryan's locker room. He tells the WWE Champion he's had a word with JBL over his unfair treatment of him. Bryan thanks him but says he doesn't need his help. He's fine alone.
- Backstage Segment: Paul Heyman and the IC Champion Curtis Axel are walking backstage. Axel complains about what Reigns did. Heyman says he will sort this out.
- The Great Khali & Tensai defeated Xavier Woods & R-Truth (Time of contest - 06:33) Tensai pins Woods after hitting the Running Senton.
- Backstage Segment: JBL sarcastically wishes Daniel Bryan luck in his match.
- Kane defeated WWE Champion Daniel Bryan in a non title No Disqualification match to qualify for the Elimination Chamber match (Time of contest - 14:03) Kane wins the match by reversing a running knee attempt from Bryan in to a Chokeslam on to a steel chair.
- After the match, Kane removes his mask. The show ends with an unmasked Kane standing over Daniel Bryan.
Here are the match results:
1. CM Punk defeated The Miz to qualify for the Elimination Chamber match
2. The Intellectual Americans (c) defeated The Money Makers to retain the World Tag Team Championship
3. Divas Champion Natalya defeated Tamina Snuka in a non title match
4. Ryback & Fandango defeated Intercontinental Champion Curtis Axel & Roman Reigns
5. The Great Khali & Tensai defeated Xavier Woods & R-Truth
6. Kane defeated WWE Champion Daniel Bryan in a non title No Disqualification match to qualify for the Elimination Chamber match
Here is the current New Years Revolution card:
1. Daniel Bryan (c) vs CM Punk vs Kane vs TBC vs TBC vs TBC in an Elimination Chamber match for the WWE Championship


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Register now for free, or sign in with any of these services:
Thanks BowdenFan22!
I was trying to convey the scenarios that are laid out on the messages boards every other day. I didn't want this to be another "Joe Must Go" article. That wasn't my intent for this article and I find those articles to be a dime a dozen.
As for the Bama game. I have received some emails and Tweets saying how awesome PSU was for the traveling Bama fans. They raved about PSU!
Thanks Bill!
I don't know about that. The students have always seemed to be good. Student section everywhere are a little rough on opposing teams.
Sorry, Endzone might now be what the Bama fans are thinking. Although, it is a fan favorite.
You can always reach me at firstname.lastname@example.com. Love your feedback!
I didn't say that Iowa isn't a good program. Like BowdenFan, I have a lot of respect for them. I was merely pointing out how the Penn State message boards implode after the Iowa games of the past five years. Every time a "Paterno Replacement" discussion takes place, Ferentz's name is always tossed around.
Thanks for reading,
I will take the last name Calzone under advisement. So far, everyone believes I should stick with Canz and nothing else.
I promise you that if that were to happen, I would go on a rant of epic proportions in a post.
Yes, the mythical Southern Pipeline...
Take a look at my Delopplelionitis post. You get the homer angle there.
First off, there will never be another Carnac the Magnificent. Secondly, this one was a little tougher to write, but I was going for accuracy and satire.
Mikey Calzone has always been a favorite of mine!
I was merely pointing out the cyclical nature of how good the Penn State defensive line has become over the last decade. PSU now averages an All American every other year. This year PSU is due for one and I think there is no surprise that Still may be the next guy to step up.
Thanks for reading!
I wasn't trying to attract readers by deception, but I see your point. I will be mindful of it in future posts.
To your point, it's on point. I personally haven't seen succession plans work all that well. Penn State has an interesting staff dynamic (from the outside), which is why it could go either way. However, I think if one were named, it would upset the staff and a lot of alumni.
It isn't an article, it's a blog post. My blog posts aren't of a serious nature, at times.
Thanks for reading,
I think we are all breathing a sigh of relief right now.
I have heard ideas about a savings account or better stipends, so far the overwhelming response has been to not pay them. Keep the ideas coming.


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Tag Archives: beaches
Taste of Summer "Blues" at Greenfield State Park
It's the beginning of another summer at Greenfield State Park, marked by its signature sights, smells, sounds, tastes, and feel. My skin sizzled under the simmering sun while a smokey scent of burgers and hot dogs on the grill wafted … Continue reading
Exploring Clough State Park
Clough State Park – June 10, 2011 Whether you like to hike, bike, paddle or swim, Clough State Park is your place to explore. The park lies along the 150-acre Everett Lake that was formed in 1963 by the … Continue reading
Posted in The NH State Park Experience | Tagged beaches, bike, Clough State Park, Everrett Dam, Everrett Lake, hike, paddle, rope swing, single-track, swimming, trails | 2 Comments
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© 2015 NH Department of Resources and Economic Development | 172 Pembroke Road P.O. Box 1856 Concord, NH 03302-1856 | T: (603) 271-3556 F: (603) 271-3553


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This week marks the 20th anniversary of the Disney animated classic "The Lion King." Relive the music, the lion lovin', and the heartbreak that scarred a generation of children. Hakuna matata!!
Huge thanks to the folks at AVbyte for doing the music and vocals! Please go over and subscribe to their channel – they do awesome musicals all year round! http://youtube.com/avbyte
ScreenJunkies was excited to team up with Made Man, who is honoring Dad all month long. June is #ForFathers: http://mademan.com/for-fathers
Consider posting a comment.


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The Lions have always been a huge part of your life. You were wearing team-spirited attire before you can remember. It's no secret that your heart will always beat with Lions pride – that's why this Heart and Soul T-shirt is perfect for you! This soft cotton tee features "Detroit" lettering arched over the Lions' logo, along with the team name printed across the chest. It is a perfect way to show everyone that your loyalty will always lie with Detroit!
- 100% Cotton fabric
- Imported
- Lightweight ribbed T-shirt
- Officially licensed NFL product
- Rib-knit collar
- Screen print graphics
Reviewed by 2 customers
Sort by
- Authentic Look
- Great Fit
- Shows Off Team Pride
- Not Made In The Usa
Best Uses
- Anytime
Comments about Detroit Lions Heart and Soul T-Shirt - Light Blue:
Love the shirt. My only complaint is where it is made. I prefer to purchase made in the USA products, this is not one of those products. Would buy more if it was made in the USA!
- Authentic Look
- Quality Construction
- Shows Off Team Pride
- Stylish Design
Best Uses
- Anytime
- Watching The Game on TV
Comments about Detroit Lions Heart and Soul T-Shirt - Light Blue:
I love the color and the style, and the price was reasonable. The service was also very good.
Special event items are produced by manufacturers only after the outcome of a game or event. These are advanced sale items and will ship immediately after they are received in our warehouse.
Manufacturer direct items are shipped directly from the manufacturer. These items are not available for international or expedited shipping.
Customized items can be personalized with options such as your name, your favorite number, and/or designs. Some options may be limited by league rules.


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ST. PAUL, Minn. - Just in time for the regular season opener on Thursday, theSt. Paul Saints have unveiled the name of their pig mascot.
Unlike previous years, there are two mascots for the 2012 season.
Their names are "Kim Lardashian" and "Kris Hamphries." The names play off the 72-day marriage of basketball player and Minnesota-native Kris Humphries and reality star Kim Kardashian.
The Saints will open the season against the Gary Southshore Railcats. It will also be Military Appreciation Night.


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Sunday, March 29, 2015
10 comments
Sunday, September 14, 2014
15 comments
I've been thinking about "starting over" a lot this weekend. No...don't panic...not ME starting over...but rather the concept of staring over. It happens to so many of us. We start strong, we make a little or even a LOT of progress, we slip, an... Read more
Sunday, March 30, 2014
13 comments
I'm proud of myself for setting this goal and accomplishing it and (mostly) I'm so happy it's over. For years I said I would NEVER do more than 5K...and now I am a half marathoner.
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Thursday, February 20, 2014
10 comments
Saturday, February 08, 2014
11 comments
I am well into my 5th year of maintenance. I know the odds are in my favor that I will keep the 60 pounds off that I lost in 2008. I am fully aware of the struggle, and how awesome it is to be a long term weight loss maintainer.
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Saturday, February 01, 2014
13 comments
I've always wanted to do it, but never thought I could...today I DID IT! Thank you sparkpeople! I would have NEVER done this if I hadn't found this web site and changed my life! 9.3 miles over two bridges and an overpass!
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Friday, January 10, 2014
15 comments
Sunday, December 08, 2013
12 comments
Tracking month to month makes it easy to see why my numbers are not going in the right direction.
Number of workouts down, % good eating days down, scale up.
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Monday, November 04, 2013
12 comments
Wednesday, October 02, 2013
8 comments
I've started keeping a monthly table of my numbers that are important to me. It may sound silly, but track... Read more
Sunday, September 29, 2013
31 comments
This is what I have recorded in my fitness minute notes this week regarding my first week using the Spark Activity Tracker. I am an avid HRM (Polar RS200) user and I do a variety of fitness activities.
Sunday, September 22, 2013
On Friday... Read more
Sunday, September 22, 2013
11 comments
Yep. I still do it. I have scheduled cheat days usually every weekend as part of my maintenance plan, but that's not what I am talking about. To me, a cheat day is having a bit more calories and carbs than I normally eat, but still making consci... Read more
Monday, September 02, 2013
11 comments
Workouts - 20 (a combination of running, RIPPED, Boot Camp and weight lifting)
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Thursday, August 01, 2013
14 comments
Workouts - 20 (a combination of running, spin, RIPPED, Boot Camp and weight lifting)
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Sunday, July 21, 2013
13 comments
Saturday: Calories-1746, Carbs-185, Fat-69, Protein-96, Fiber-28, Sodium-1684
Sunday: Calories-1646, Carbs-199, Fat-61, Protein-81, Fiber-31, Sodium 1331
Read more


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thinkin of tryin this.....just seein if anyone tryed this??? and do you like it...i have the 3.5l v6...thanks..lp
You could do it with a resonated kit, it would sound like crap with no muffler and no resonator. Picture Johnson outboard on steroids.
If you can read this, thank a Teacher.
If you can read this in English, thank a MARINE.
Sponsored by Billet Technology
Powered by Franks Racing Inc
Back to my former Cam Only Record Holder setup.
[06 300C - 77 F250 460 - 85 Ramcharger 318]
"I spent a lot of my money on booze, women and fast cars. The rest I just squandered."


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Whether a trauma is borne from personal heartbreak or a global tragedy, the road to healing is often long and painful.
Dr. David Niyonzima, who survived a 1993 violent ethnic massacre in Burundi that killed eight of his students, will share his personal journey of healing and forgiveness from 6 to 9 p.m. Oct. 7 in the Marriage and Family Therapy facility on Friends University's Wichita campus.
Jack Cole is on a mission to redeem himself for destroying more than a thousand lives as an undercover narcotics investigator for the New Jersey State Police.
He wasn't a dirty cop. He didn't break any laws. In fact, he says he ruined people's lives in the course of his duty.
"I can't tell you how many folks I sent to prison that would have gone on to have productive lives had I not intervened," Cole said as spokesman for Law Enforcement Against Prohibition (LEAP). "Ultimately, you can get over an addiction, but you'll never get over a conviction."
The Hon. G. Joseph Pierron Jr. will be the featured presenter at Friends University's Constitution Day program Sept. 23, 2013. The interactive lecture will begin at 7 p.m. in Alumni Auditorium, Davis Administration Building.
The presentation, titled "You Be the Judge," will be led by Judge Pierron, with the audience playing the litigants, lawyers and judges in a re-creation of actual United States Supreme Court cases. Audience members do not need to prepare for the program.
More than 160 Friends University students joined the Race for Freedom Sept. 7 in an effort to raise awareness and funds for ICT S.O.S., a Wichita group dedicated to combating human trafficking.
ICT S.O.S. serves as the liaison between professional groups – such as Street Outreach, EMCU and Youthville – who work with youths who are victims of human trafficking.
Kansas' poet laureate will be among several noteworthy presenters at the Kansas Alliance for the Arts in Education (KSAAE) professional development conference at the Friends University campus Sept. 21. The KSAAE works to ensure the arts are an integral part of quality pre K-12 education to promote students' personal development and academic performance. For more information about the conference, click here.
As a member of the Kansas Independent College Association (KICA), Friends University is pleased to celebrate Kansas Private College Week Sept. 16-20. The week is designed to increase awareness of independent colleges and universities in Kansas and is sponsored by KICA. For more information, click here.
Friends University's Apprentice Institute founder Dr. James Bryan Smith's book, "Hidden in Christ," focuses on the truth and affirmation he finds in Colossians 3. The Scripture "is a very rich passage, comprising a complete picture of our life in Christ," Dr. Smith says in his interview with the Wichita Eagle.
Six hundred attendees are expected to flock to Friends University for the Aprentis Conference in September to discuss how we immerse ourselves in the story of God.
The third annual Aprentis Conference will lead attendees in a three-day experience from Sept. 26-28. This year's conference is themed The Story of God and Us.
Cancer has touched so many of our lives in the same way it has touched Katrina Bilella, a graduate student from Florida State University.
In 2002, she lost her grandfather after a two-year battle with esophageal cancer, and now she's watching her aunt fight breast cancer. Inspired by the war her loved ones have waged against the disease, Bilella has enlisted as a soldier, taking on a 4,000-mile bike journey from Baltimore to San Francisco with 25 other bicyclists to raise funds to fight the disease that has affected her family so deeply.
The 34th Annual Telly Awards has honored Armstrong Chamberlin Strategic Marketing with a 2013 Bronze Telly Award for its Friends University regional TV campaign, "Are You Ready?" The campaign included television commercials and online pre-rolls, written and directed by Armstrong Chamberlin and produced by Digital Brand of Wichita.


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Implantable medical devices with elastomeric block copolymer coatings are disclosed.
1. An implantable medical device comprising a coating above a polymer surface of the device, the coating comprising:
a block copolymer including an elastic block and an anchor block, the elastic block being a random or alternating copolymer and having elastomeric behavior at physiological conditions, the anchor block being miscible with the surface polymer, wherein the surface polymer and the anchor block comprise PLLA or LPLG and wherein the block copolymer is selected from the group consisting of P(GA-co-CL)-b-PLLA, P(GA-co-CL)-b-LPLG, P(GA-co-TMC)-b-PLLA, and P(GA-co-TMC)-b-LPLG.
2. The device of
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1. Field of the Invention
This invention relates to coatings for implantable medical devices composed of block copolymers.
2. Description of the State of the Art
This invention relates to radially expandable endoprostheses, which are adapted to be implanted in a bodily lumen. An "endoprosthesis" corresponds to an artificial device that is placed inside the body. A "lumen" refers to a cavity of a tubular organ such as a blood vessel.
A stent is an example of such an endoprosthesis. Stents are generally cylindrically shaped devices, which function to hold open and sometimes expand a segment of a blood vessel or other anatomical lumen such as urinary tracts and bile ducts. Stents are often used in the treatment of atherosclerotic stenosis in blood vessels. "Stenosis" refers to a narrowing or constriction of the diameter of a bodily passage or orifice. In such treatments, stents reinforce body vessels and prevent restenosis following angioplasty in the vascular system. "Restenosis" refers to the reoccurrence of stenosis in a blood vessel or heart valve after it has been treated (as by balloon angioplasty, stenting, or valvuloplasty) with apparent success.
The treatment of a diseased site or lesion with a stent involves both delivery and deployment of the stent. "Delivery" refers to introducing and transporting the stent through a bodily lumen to a region, such as a lesion, in a vessel that requires treatment. "Deployment" corresponds to the expanding of the stent within the lumen at the treatment region. Delivery and deployment of a stent are accomplished by positioning the stent about one end of a catheter, inserting the end of the catheter through the skin into a bodily lumen, advancing the catheter in the bodily lumen to a desired treatment location, expanding the stent at the treatment location, and removing the catheter from the lumen.
In the case of a balloon expandable stent, the stent is mounted about a balloon disposed on the catheter. Mounting the stent typically involves compressing or crimping the stent onto the balloon. The stent is then expanded by inflating the balloon. The balloon may then be deflated and the catheter withdrawn. In the case of a self-expanding stent, the stent may be secured to the catheter via a constraining member such as a retractable sheath or a sock. When the stent is in a desired bodily location, the sheath may be withdrawn which allows the stent to self-expand.
The stent must be able to satisfy a number of mechanical requirements. First, the stent must be capable of withstanding the structural loads, namely radial compressive forces, imposed on the stent as it supports the walls of a vessel. Therefore, a stent must possess adequate radial strength. Radial strength, which is the ability of a stent to resist radial compressive forces, is due to strength and rigidity around a circumferential direction of the stent. Radial strength and rigidity, therefore, may also be described as, hoop or circumferential strength and rigidity.
Once expanded, the stent must adequately maintain its size and shape throughout its service life despite the various forces that may come to bear on it, including the cyclic loading induced by the beating heart. For example, a radially directed force may tend to cause a stent to recoil inward. Generally, it is desirable to minimize recoil. In addition, the stent must possess sufficient flexibility to allow for crimping, expansion, and cyclic loading. Longitudinal flexibility is important to allow the stent to be maneuvered through a tortuous vascular path and to enable it to conform to a deployment site that may not be linear or may be subject to flexure. Finally, the stent must be biocompatible so as not to trigger any adverse vascular responses.
The structure of a stent is typically composed of scaffolding that includes a pattern or network of interconnecting structural elements often referred to in the art as struts or bar arms. The scaffolding can be formed from wires, tubes, or sheets of material rolled into a cylindrical shape. The scaffolding is designed so that the stent can be radially compressed (to allow crimping) and radially expanded (to allow deployment). A conventional stent is allowed to expand and contract through movement of individual structural elements of a pattern with respect to each other.
Furthermore, it may be desirable for a stent to be biodegradable. In many treatment applications, the presence of a stent in a body may be necessary for a limited period of time until its intended function of, for example, maintaining vascular patency and/or drug delivery is accomplished. Therefore, stents fabricated from biodegradable, bioabsorbable, and/or bioerodable materials such as bioabsorbable polymers should be configured to completely erode only after the clinical need for them has ended.
Additionally, a medicated stent may be fabricated by coating the surface of either a metallic or polymeric scaffolding with a polymeric carrier that includes an active or bioactive agent or drug. Polymeric scaffolding may also serve as a carrier of an active agent or drug. Potential problems with therapeutic coatings for polymeric implantable medical devices, such as stents, include insufficient toughness, slow degradation rate, and poor adhesion.
Various embodiments of the present invention include an implantable medical device a coating above a polymer surface of the device, the coating comprising: a block copolymer including an elastic block and an anchor block, the elastic block being a random or alternating copolymer and having elastomeric behavior at physiological conditions, the anchor block being miscible with the surface polymer.
Various embodiments of the present invention include an implantable medical device with a coating having an elastomeric block copolymer above a polymeric surface of the device. The polymeric surface may be a surface of a polymer coating disposed above a substrate that can be composed of metal, polymer, ceramic, or other suitable material. Alternatively, the polymeric surface may be a surface of a polymeric substrate. "Above" a surface is defined as higher than or over a surface measured along an axis normal to the surface, but not necessarily in contact with the surface.
The present invention may be applied to implantable medical devices including, but not limited to, self-expandable stents, balloon-expandable stents, stent-grafts, and grafts (e.g., aortic grafts), and generally expandable tubular devices for various bodily lumen or orifices. A stent can have a scaffolding or a substrate that includes a pattern of a plurality of interconnecting structural elements or struts.
In some embodiments, a stent may be fabricated by laser cutting a pattern on a tube or a sheet rolled into a tube. Representative examples of lasers that may be used include, but are not limited to, excimer, carbon dioxide, and YAG. In other embodiments, chemical etching may be used to form a pattern on a tube.
An implantable medical device can be made partially or completely from a biodegradable, bioabsorbable, biostable polymer, or a combination thereof. A polymer for use in fabricating an implantable medical device can be biostable, bioabsorbable, biodegradable or bioerodable. Biostable refers to polymers that are not biodegradable. The terms biodegradable, bioabsorbable, and bioerodable are used interchangeably and refer to polymers that are capable of being completely degraded and/or eroded when exposed to bodily fluids such as blood and can be gradually resorbed, absorbed, and/or eliminated by the body. The processes of breaking down and absorption of the polymer can be caused by, for example, hydrolysis and metabolic processes.
As indicated above, a medicated implantable medical device, such as a stent, may be fabricated by coating the surface of a stent with a drug. For example, a device can have a coating including a drug dispersed in a polymeric carrier disposed over a substrate of the stent. Such a coating layer may be formed by applying a coating material to a substrate of an implantable medical device, such as a stent. The coating material can be a polymer solution and a drug dispersed in the solution. The coating material may be applied to the stent by immersing the stent in the coating material, by spraying the material onto the stent, or by other methods known in the art. The solvent in the solution is then removed, for example, by evaporation, leaving on the stent surfaces a polymer coating impregnated with the drug.
Stents are typically subjected to stress during use. "Use" includes manufacturing, assembling (e.g., crimping a stent on balloon), delivery of a stent through a bodily lumen to a treatment site, deployment of a stent at a treatment site, and treatment after deployment. Both the underlying scaffolding or substrate and the coating experience stress that result in strain in the substrate and coating. In particular, localized portions of the stent's structure undergo substantial deformation. For example, the apex regions of bending elements 130, 140, and 150 in
Furthermore, polymer substrates and polymer-based coatings may be particularly vulnerable to mechanical instability during use of a stent. Such mechanical instability for coatings can include fracture and detachment from a substrate, for exampling, peeling. Some polymers may be susceptible to such mechanical instability due to insufficient toughness at high deformations. Additionally, detachment of coatings may be due to poor adhesion of the polymer-based coating to the substrate or another polymer layer. Therefore, polymer-based coatings are highly susceptible to tearing or fracture, and/or detachment, especially at regions subjected to relatively high stress and strain. Thus, it is important for a polymer-based coating to (1) be tough and have a high resistance to cracking and (2) have good adhesion with an underlying layer or substrate and to have a high resistance to detachment in the range of deformations that occur during crimping, during deployment of a stent, and after deployment.
As indicated above, a device may be composed in whole or in part of materials that degrade, erode, or disintegrate through exposure to physiological conditions within the body until the treatment regimen is completed. The device may be configured to disintegrate and disappear from the region of implantation once treatment is completed. The device may disintegrate by one or more mechanisms including, but not limited to, dissolution and chemical breakdown. The duration of a treatment period depends on the bodily disorder that is being treated. For illustrative purposes only, in treatment of coronary heart disease involving use of stents in diseased vessels, the duration can be in a range from about a month to a few years. However, the duration is typically in a range from about six to twelve months. Thus, it is desirable for polymer-based coatings and substrates of an implantable medical device, such as a stent, to have a degradation time at or near the duration of treatment. Degradation time refers to the time for an implantable medical device to substantially or completely erode away from an implant site.
Embodiments of the present invention include an implantable medical device including a coating above a polymer surface of the device, the coating including a block copolymer including an elastic block and an anchor block. The elastic block exhibits elastomeric or rubbery behavior at physiological conditions. In some embodiments, the elastic block, the anchor block, or both can be bioabsorable polymers. In addition, the anchor block is miscible with the surface polymer. In some embodiments, all or a majority of the coating may be the block copolymer. Additionally, the coating can be a therapeutic layer with an active agent or drug mixed or dispersed within the block copolymer.
In such embodiments, the block copolymer can have more than one elastic block and more than one anchor block. In one embodiment, the block copolymer can have an elastic block on one end and an anchor block at another end. In another embodiment, the block copolymer can have an elastic block between two anchor blocks or anchor block between two elastic blocks.
In certain embodiments, the block copolymer coating is disposed directly over the surface of a polymer substrate of a device, such as a stent scaffolding.
In other embodiments, the block copolymer coating can be over a polymer coating layer that is disposed over a substrate.
In some embodiments, the block copolymer coating exhibits a rubbery or elastomeric behavior at physiological conditions. An "elastomeric" or "rubbery" polymer refers to a polymer that exhibits elastic deformation through all or most of a range of deformation. Physiological conditions include, but are not limited to, human body temperature, approximately 37� C. The elastic block of the block copolymer is an elastomeric or rubbery polymer that allows or provides the elastomeric or rubbery properties of the coating. Such elastomeric properties provide the coating with a high fracture toughness during use of a device such as a stent. In some embodiments, the elastic blocks can have glass transition temperature (Tg) below body temperature. Additionally, the block copolymer may be completely or substantially amorphous.
In some embodiments, the elastic block of the block copolymer includes functional groups or units that provide the rubbery or elastic properties to the block copolymer. In such embodiments, the elastic block can be a random or alternating copolymer that includes units, referred to herein as "elastic units," that form elastic or rubbery polymers at physiological conditions. Biodegradable polymers that are elastomer or rubber at physiological conditions include, but are not limited to, polycaprolactone (PCL), poly(tetramethyl carbonate) (PTMC), poly(4-hydroxy butyrate) (PHB), and polydioxanone (PDO). Some embodiments of the elastic blocks of the block copolymer can include caprolactone (CL), tetramethyl carbonate (TMC), 4-hydroxy butyrate (HB), dioxanone (DO), or a combination thereof. Exemplary elastic blocks can include at least two types of functional units, for example, P(CL-co-TMC), P(CL-co-HB), P(CL-DO), etc.
In additional embodiments, the elastic block can be a copolymer of at least one elastic unit and an additional unit. A homopolymer of the additional unit may be a glassy polymer with a Tg above body temperature. The additional unit may be selected so that it increases the degradation rate of the copolymer. For example, the additional "fast eroding" units may be more hydrophilic or more hydrolytically active than the elastic unit. Additionally, the additional unit may have acidic and hydrophilic degradation products. Since the rate of the hydrolysis reaction tends to increase as the pH decreases, acidic degradation products can increase the degradation rate of the block copolymer. Glycolide (GA) units, for example, have acidic degradation products which can increase the degradation rate of the coating. Exemplary elastic blocks can include P(CL-co-GA), P(GA-co-TMC), P(GA-DO), etc.
In some embodiments, the toughness and degradation rate of the block copolymer coating can be adjusted by the ratio of elastic and non-elastic units. As the ratio of CL, for example, increases in P(GA-co-CL) segments, the block copolymer becomes more flexible and tougher. The Tg of the elastic block can be tuned to a desired value by adjusting the ratio of component monomers. Additionally, the degradation rate of the block copolymer coating can be increased by increasing the fraction of "fast eroding units," such as GA, in the elastic blocks. In exemplary embodiments, the P(GA-co-CL) segments can have up to 1 wt %, 5 wt %, 20 wt %, or 50 wt % GA units.
As discussed above, the anchor block of the block copolymer can be miscible with the surface polymer. In one embodiment, the anchor block can have the same chemical composition as the surface polymer. Alternatively, the anchor block can have a chemical composition different from the surface polymer, but similar enough so that the anchor block is miscible with the surface polymer. In an exemplary embodiment, the block copolymer can have a PLLA anchor block and be disposed over a PLLA surface, which can be the surface of a PLLA substrate.
In certain embodiments, the anchor block can be a copolymer. In such embodiments, the composition of the anchor blocks of the block copolymer coating can be selected so that the anchor block is miscible with the surface polymer. In addition, the units of the copolymer can be selected to adjust the degradation rate of the block copolymer. In one embodiment, the anchor block can include units that are more hydrolytically active or hydrophilic than other units to increase the degradation rate of the coating. In an exemplary embodiment, the anchor block can be poly(L-lactide-co-glycolide) (LPLG). In such an embodiment, the surface polymer can be LPLG. The composition of LLA and GA in the anchor block can be adjusted so that the LPLG anchor block is miscible with the LPLG surface polymer. In some embodiments, the surface polymer can be a copolymer having a high percentage of LLA units, for example, at least 60 wt %, 70 wt %, or 80 wt % LLA units.
In further embodiments, the block copolymer coating can be applied to a polymer surface so that at least some of the elastomeric block copolymer is mixed within the surface polymer. In particular, at least the anchor blocks can be mixed within the surface polymer. It is believed that an interfacial region between the coating and the surface polymer can have block copolymer mixed with surface polymer. The anchor blocks of the block copolymer act as a compatibilizer that strengthens the bond between the coating and the coated surface. The interfacial region can enhance the adhesion of the block copolymer coating to the polymer substrate or polymer surface layer, in general.
The enhanced adhesion can allow the use of a tough, high fracture resistant coating that may otherwise have poor adhesion to a polymer substrate of a device. The polymer material for a substrate of a device, such as a stent, may be selected primarily on the basis of strength and stiffness so that the stent substrate can provide support for a lumen. Such substrate polymers tend to be crystalline or semi-crystalline polymers that are glassy or have a Tg above body temperature. Tough, elastomeric polymers may not necessarily have good adhesion with such a substrate. Embodiments of the block copolymer with an anchor block allow the use of a tough, high fracture resistant coating over a glassy substrate. Such glassy substrate polymers include PLLA and LPLG.
Exemplary elastomeric block copolymers include, but are not limited to, P(CA-co-TMC)-b-PLLA, P(CA-co-TMC)-b-LPLG, P(CA-co-GA)-b-PLLA, P(CA-co-GA)-b-LPLG, P(TMC-co-GA)-b-PLLA, P(TMC-co-GA)-b-LPLG.
In exemplary embodiments, the molecular weight of the elastic blocks can be between 20 kg/mol and 150 kg/mol, or greater than 150 kg/mol. In exemplary embodiments, the molecular weight of the anchor blocks can be between 20 kg/mol_and 150 kg/mol, or greater than 150 kg/mol. The relative weight percent of the elastic blocks and the anchor blocks can be between 1:5 and 5:1.
In some embodiments, the block copolymer coating can include a dispersed polymer phase. In such embodiments, the anchor block can have a high enough molecular weight that a dispersed anchor block phase is formed within an elastomeric phase composed of the elastic blocks. In these embodiments, the anchor block can be a crystalline or semicrystalline polymer. The dispersed phase can be crystalline or semi-crystalline polymer regions that are dispersed within an amorphous elastomeric phase. The crystalline regions can be used to modify the delivery rate of a dispersed drug from the coating. The crystalline regions tend to increase the delivery rate of drug from the coating.
Embodiments of the elastomeric block copolymers disclosed herein can be formed by solution-based polymerization. Other methods of forming the block copolymers are also possible, such as, without limitation, melt phase polymerization.
Some embodiments of the solution polymerization involve forming the elastic blocks first and then the anchor blocks. In such embodiments, a solution is prepared including the elastic units for the elastic blocks, an appropriate solvent, an appropriate initiator, and catalyst in which the elastic blocks are formed from the monomers. The anchor block units for the anchor block and catalyst are then added to the solution to form anchor blocks that are bonded to the elastic blocks. The elastomeric block copolymer can be removed from the solution through precipitation in a non-solvent of the elastomeric block copolymer. The solvent(s) for the reaction mixture can be selected so that the elastic blocks formed are soluble in the solvent(s) to allow the elastic blocks to copolymerize with anchor blocks in solution.
For example, to prepare P(GA-co-CL)-b-PLLA block copolymer, P(GA-co-CL) elastic blocks are formed in a solution containing GA and CL monomers, a dodecanol initiator, and stannous octoate catalyst in a xylene solvent. L-lactide monomers can then be added to the solution. The L-lactide monomers react with P(GA-co-CL) to form P(GA-co-CL)-b-PLLA. The solution can then be added to methanol, which is a non-solvent for the formed block copolymer, to precipitate the elastomeric block copolymer from solution.
In other embodiments of solution polymerization, elastomeric block copolymers can be formed by reacting elastic blocks swollen with a solvent that contains anchor block monomers. The elastic blocks are swollen by a solvent after they are formed so that they can react with anchor block monomers. One of skill in the art can select a solvent that swells but does not dissolve the elastic blocks.
In one embodiment, the solvent for use in synthesizing the elastomeric block copolymer is devoid of alcohol functional groups. Such alcohol groups may act as initiators for chain growth in the polymer. Solvents used to synthesize the elastomeric block copolymer include, but are not limited to, chloroform, toluene, xylene, and cyclohexane.
Other embodiments of the solution polymerization involve forming the anchor blocks first and then the elastic blocks.
The block copolymer coating may be formed over an implantable medical device, such as a stent, by applying a coating material to a polymer surface of the device. The coating material can be a solution including the block copolymer. The solution can further include an active agent or drug dissolved in a solvent. As discussed above, the coating material may be applied to the stent by immersing the device in the coating material, by spraying the composition onto the device, or by other methods known in the art. The solvent in the solution is removed, leaving on the device surfaces the elastomeric block polymer coating and optionally drug dispersed within the polymer.
Drying or solvent removal can be performed by allowing the solvent to evaporate at room or ambient temperature. Depending on the volatility of the particular solvent employed, the solvent can evaporate essentially upon contact with the stent. Alternatively, the solvent can be removed by subjecting the coated stent to various drying processes. Drying time can be decreased to increase manufacturing throughput by heating the coated stent. For example, removal of the solvent can be induced by baking the stent in an oven at a mild temperature (e.g., 50� C.) for a suitable duration of time (e.g., 2-4 hours) or by the application of warm air. In an embodiment, a substantial portion of solvent removed may correspond to less than 5%, 3%, or more narrowly, less than 1% of solvent remaining after drying. Depositing a coating of a desired thickness in a single coating stage can result in an undesirably nonuniform surface structure and/or coating defects. Therefore, a coating process can involve multiple repetitions of application, for example, by spraying a plurality of layers.
In some embodiments, the solvent of the coating material is also a solvent for the surface polymer on which the coating material is applied. Specifically, a "solvent" for a given polymer can be defined as a substance capable of dissolving or dispersing the polymer or capable of at least partially dissolving or dispersing the polymer to form a uniformly dispersed mixture at the molecular- or ionic-size level. The solvent should be capable of dissolving at least 0.1 mg of the polymer in 1 ml of the solvent, and more narrowly 0.5 mg in 1 ml at ambient temperature and ambient pressure. The solvent in the coating material can dissolve at least a portion of the surface polymer upon application of the coating material to the polymer surface.
Due to dissolution of a portion of the surface polymer, the coating material near the surface of the surface polymer includes dissolved surface polymer in addition to the elastic block copolymer from the coating material. It is believed that upon removal of the solvent, an interfacial region, as depicted in
In other embodiments, the solvent in the coating material can be capable of swelling the surface polymer, but is incapable or substantially incapable of dissolving the surface polymer. A solvent that is capable of swelling the surface polymer and is incapable or substantially incapable of dissolving the polymer is understood to mean a sample of the surface polymer swells when immersed in the solvent and the swollen sample of the surface polymer remains in the solvent with a negligible loss of mass for an indefinite period of time at conditions of ambient temperature and pressure.
Solvents for polymers can be found in standard texts (e.g., see Fuchs, in Polymer Handbook, 3rd Edition and Deasy, Microencapsulation and Related Drug Processes, 1984, Marcel Dekker, Inc., New York.) The ability of a polymer to swell and to dissolve in a solvent can be estimated using the Cohesive Energy Density Concept (CED) and related solubility parameter values as discussed by Deasy and can be found in detail in the article by Grulke in Polymer Handbook.
In some embodiments, a polymeric substrate or polymeric surface coating layer can be pretreated with a solvent that dissolves or swells the surface polymer prior to applying a coating material.
In certain embodiments, the coating material solvent is different from the pretreatment solvent. The use of a different solvent for the coating material and the pretreating can provide a degree of flexibility to the coating process. Generally, a treatment with a medicated stent may require a particular drug coating on a coating of a medicated stent. A drug may have an undesirably low or negligible solubility in a selected group of solvents that can dissolve or swell the surface polymer. Thus, a drug coating formed using such a solvent can have an undesirably low concentration of drug. A suitable pretreatment solvent can be used to dissolve or swell the surface polymer and a different solvent can be used as a coating solvent, in which the drug has an acceptable solubility. In general, a required solubility of a drug in a coating solvent is determined by the drug loading required of a particular treatment regimen. Specifically, it is desirable for a drug to have solubility of at least 1 wt % in a solvent for use as a coating material solvent for forming a drug-polymer layer on a stent.
In other embodiments, an elastomeric block copolymer coating can be a primer layer over a polymer substrate or coating layer. The elastomeric block copolymer coating can act as a primer layer for a drug-polymer coating layer over the primer layer. The elastomeric block copolymer primer layer may be formed above a polymeric surface, as described above. The primer coating material can include an elastic block copolymer dissolved in a solvent that can dissolve or swell the surface polymer. A drug-polymer layer can then be formed over the elastomeric block copolymer primer layer. The drug coating material may include a polymer that is different from the elastomeric block copolymer and a solvent that is different from the primer coating material solvent.
In general, representative examples of polymers that may be used to fabricated a substrate of and coatings for an implantable device include, but are not limited to, poly(N-acetylglucosamine) (Chitin), Chitosan, poly(hydroxyvalerate), poly(lactide-co-glycolide), poly(hydroxybutyrate), poly(hydroxybutyrate-co-valerate), polyorthoester, polyanhydride, poly(glycolic acid), poly(glycolide), poly(L-lactic acid), poly(L-lactide), poly(D,L-lactic acid), poly(L-lactide-co-glycolide); poly(D,L-lactide), poly(caprolactone), poly(trimethylene carbonate), polyethylene amide, polyethylene acrylate, poly(glycolic acid-co-trimethylene carbonate), co-poly(ether-esters) (e.g. PEO/PLA), polyphosphazenes, biomolecules (such as fibrin, fibrinogen, cellulose, starch, collagen and hyaluronic acid), polyurethanes, silicones, polyesters, polyolefins, polyisobutylene and ethylene-alphaolefin copolymers, acrylic polymers and copolymers other than polyacrylates, vinyl halide polymers and copolymers (such as polyvinyl chloride), polyvinyl ethers (such as polyvinyl methyl ether), polyvinylidene halides (such as polyvinylidene chloride), polyacrylonitrile, polyvinyl ketones, polyvinyl aromatics (such as polystyrene), polyvinyl esters (such as polyvinyl acetate), acrylonitrile-styrene copolymers, ABS resins, polyamides (such as Nylon 66 and polycaprolactam), polycarbonates, polyoxymethylenes, polyimides, polyethers, polyurethanes, rayon, rayon-triacetate, cellulose, cellulose acetate, cellulose butyrate, cellulose acetate butyrate, cellophane, cellulose nitrate, cellulose propionate, cellulose ethers, and carboxymethyl cellulose.
Additional representative examples of polymers that may be especially well suited for use in embodiments of the present invention include ethylene vinyl alcohol copolymer (commonly known by the generic name EVOH or by the trade name EVAL), poly(butyl methacrylate), poly(vinylidene fluoride-co-hexafluororpropene) (e.g., SOLEF 21508, available from Solvay Solexis PVDF, Thorofare, N.J.), polyvinylidene fluoride (otherwise known as KYNAR, available from ATOFINA Chemicals, Philadelphia, Pa.), ethylene-vinyl acetate copolymers, and polyethylene glycol.
For the purposes of the present invention, the following terms and definitions apply:
For the purposes of the present invention, the following terms and definitions apply:
The "glass transition temperature," Tg, is the temperature at which the amorphous domains of a polymer change from a brittle vitreous state to a solid deformable, ductile, or rubbery state at atmospheric pressure. In other words, the Tg corresponds to the temperature where the onset of segmental motion in the chains of the polymer occurs. When an amorphous or semicrystalline polymer is exposed to an increasing temperature, the coefficient of expansion and the heat capacity of the polymer both increase as the temperature is raised, indicating increased molecular motion. As the temperature is raised the actual molecular volume in the sample remains constant, and so a higher coefficient of expansion points to an increase in free volume associated with the system and therefore increased freedom for the molecules to move. The increasing heat capacity corresponds to an increase in heat dissipation through movement. Tg of a given polymer can be dependent on the heating rate and can be influenced by the thermal history of the polymer. Furthermore, the chemical structure of the polymer heavily influences the glass transition.
"Stress" refers to force per unit area, as in the force acting through a small area within a plane. Stress can be divided into components, normal and parallel to the plane, called normal stress and shear stress, respectively. True stress denotes the stress where force and area are measured at the same time. Conventional stress, as applied to tension and compression tests, is force divided by the original gauge length.
"Strength" refers to the maximum stress along an axis which a material will withstand prior to fracture. The ultimate strength is calculated from the maximum load applied during the test divided by the original cross-sectional area.
"Strain" refers to the amount of elongation or compression that occurs in a material at a given stress or load.
"Elongation" may be defined as the increase in length in a material which occurs when subjected to stress. It is typically expressed as a percentage of the original length.
"Toughness" is the amount of energy absorbed prior to fracture, or equivalently, the amount of work required to fracture a material. One measure of toughness is the area under a stress-strain curve from zero strain to the strain at fracture. Thus, a brittle material tends to have a relatively low toughness.
Drugs or therapeutic active agent(s) can include anti-inflammatories, antiproliferatives, and other bioactive agents.
An antiproliferative agent can be a natural proteineous agent such as a cytotoxin or a synthetic molecule. Preferably, the active agents include antiproliferative substances such as actinomycin D, or derivatives and analogs thereof (manufactured by Sigma-Aldrich 1001 West Saint Paul Avenue, Milwaukee, Wis. 53233; or COSMEGEN available from Merck) (synonyms of actinomycin D include dactinomycin, actinomycin IV, actinomycin I1, actinomycin X1, and actinomycin C1), all taxoids such as taxols, docetaxel, and paclitaxel, paclitaxel derivatives, all olimus drugs such as macrolide antibiotics, rapamycin, everolimus, structural derivatives and functional analogues of rapamycin, structural derivatives and functional analogues of everolimus, FKBP-12 mediated mTOR inhibitors, biolimus, perfenidone, prodrugs thereof, co-drugs thereof, and combinations thereof. Representative rapamycin derivatives include 40-O-(3-hydroxy)propyl-rapamycin, 40-O-[2-(2-hydroxy)ethoxy]ethyl-rapainycin, or 40-O-tetrazole-rapamycin, 40-epi-(N1-tetrazolyl)-rapamycin (ABT-578 manufactured by Abbott Laboratories, Abbott Park, Ill.), prodrugs thereof, co-drugs thereof, and combinations thereof. In one embodiment, the anti-proliferative agent is everolimus.
An anti-inflammatory drug can be a steroidal anti-inflammatory agent, a nonsteroidal anti-inflammatory agent, or a combination thereof. In some embodiments, anti-inflammatory drugs include, but are not limited to, alclofenac, alclometasone dipropionate, algestone acetonide, alpha amylase, amcinafal, amcinafide, amfenac sodium, amiprilose hydrochloride, anakinra, anirolac, anitrazalen, apazone, balsalazide disodium, bendazac, benoxaprofen, benzydamine hydrochloride, bromelains, broperamole, budesonide, carprofen, cicloprofen, cintazone, cliprofen, clobetasol propionate, clobetasone butyrate, clopirac, cloticasone propionate, cormethasone acetate, cortodoxone, deflazacort, desonide, desoximetasone, dexamethasone dipropionate, diclofenac potassium, diclofenac sodium, diflorasone diacetate, diflumidone sodium, diflunisal, difluprednate, diftalone, dimethyl sulfoxide, drocinonide, endrysone, enlimomab, enolicam sodium, epirizole, etodolac, etofenamate, felbinac, fenamole, fenbufen, fenclofenac, fenclorac, fendosal, fenpipalone, fentiazac, flazalone, fluazacort, flufenamic acid, flumizole, flunisolide acetate, flunixin, flunixin meglumine, fluocortin butyl, fluorometholone acetate, fluquazone, flurbiprofen, fluretofen, fluticasone propionate, furaprofen, furobufen, halcinonide, halobetasol propionate, halopredone acetate, ibufenac, ibuprofen, ibuprofen aluminum, ibuprofen piconol, ilonidap, indomethacin, indomethacin sodium, indoprofen, indoxole, intrazole, isoflupredone acetate, isoxepac, isoxicam, ketoprofen, lofemizole hydrochloride, lomoxicam, loteprednol etabonate, meclofenamate sodium, meclofenamic acid, meclorisone dibutyrate, mefenamic acid, mesalamine, meseclazone, methylprednisolone suleptalnate, momiflumate, nabumetone, naproxen, naproxen sodium, naproxol, nimazone, olsalazine sodium, orgotein, orpanoxin, oxaprozin, oxyphenbutazone, paranyline hydrochloride, pentosan polysulfate sodium, phenbutazone sodium glycerate, pirfenidone, piroxicam, piroxicam cinnamate, piroxicam olamine, pirprofen, prednazate, prifelone, prodolic acid, proquazone, proxazole, proxazole citrate, rimexolone, romazarit, salcolex, salnacedin, salsalate, sanguinarium chloride, seclazone, sermetacin, sudoxicam, sulindac, suprofen, talmetacin, talniflumate, talosalate, tebufelone, tenidap, tenidap sodium, tenoxicam, tesicam, tesimide, tetrydamine, tiopinac, tixocortol pivalate, tolmetin, tolmetin sodium, triclonide, triflumidate, zidometacin, zomepirac sodium, aspirin (acetylsalicylic acid), salicylic acid, corticosteroids, glucocorticoids, tacrolimus, pimecorlimus, prodrugs thereof, co-drugs thereof, and combinations thereof. In one embodiment, the anti-inflammatory agent is clobetasol.
Alternatively, the anti-inflammatory may be a biological inhibitor of proinflammatory signaling molecules. Anti-inflammatory biological agents include antibodies to such biological inflammatory signaling molecules.
In addition, drugs or active can be other than antiproliferative agents or anti-inflammatory agents. These active agents can be any agent which is a therapeutic, prophylactic, or a diagnostic agent. In some embodiments, such agents may be used in combination with antiproliferative or anti-inflammatory agents. These agents can also have anti-proliferative and/or anti-inflammatory properties or can have other properties such as antineoplastic, antiplatelet, anti-coagulant, anti-fibrin, antithrombonic, antimitotic, antibiotic, antiallergic, antioxidant, and cystostatic agents. Examples of suitable therapeutic and prophylactic agents include synthetic inorganic and organic compounds, proteins and peptides, polysaccharides and other sugars, lipids, and DNA and RNA nucleic acid sequences having therapeutic, prophylactic or diagnostic activities. Nucleic acid sequences include genes, antisense molecules which bind to complementary DNA to inhibit transcription, and ribozymes. Some other examples of other bioactive agents include antibodies, receptor ligands, enzymes, adhesion peptides, blood clotting factors, inhibitors or clot dissolving agents such as streptokinase and tissue plasminogen activator, antigens for immunization, hormones and growth factors, oligonucleotides such as antisense oligonucleotides and ribozymes and retroviral vectors for use in gene therapy. Examples of antineoplastics and/or antimitotics include methotrexate, azathioprine, vincristine, vinblastine, fluorouracil, doxorubicin hydrochloride (e.g. Adriamycin� from Pharmacia & Upjohn, Peapack N.J.), and mitomycin (e.g. Mutamycin� from Bristol-Myers Squibb Co., Stamford, Conn.). Examples of such antiplatelets, anticoagulants, antifibrin, and antithrombins include sodium heparin, low molecular weight heparins, heparinoids, hirudin, argatroban, forskolin, vapiprost, prostacyclin and prostacyclin analogues dextran, D-phe-pro-arg-chloromethylketone (synthetic antithrombin), dipyridamole, glycoprotein Ib/IIIa platelet membrane receptor antagonist antibody, recombinant hirudin, thrombin inhibitors such as Angiomax � (Biogen, Inc., Cambridge, Mass.), calcium channel blockers (such as nifedipine), colchicine, fibroblast growth factor (FGF) antagonists, fish oil (omega 3-fatty acid), histamine antagonists, lovastatin (an inhibitor of HMG-CoA reductase, a cholesterol lowering drug, brand name Mevacor� from Merck & Co., Inc., Whitehouse Station, N.J.), monoclonal antibodies (such as those specific for Platelet-Derived Growth Factor (PDGF) receptors), nitroprusside, phosphodiesterase inhibitors, prostaglandin inhibitors, suramin, serotonin blockers, steroids, thioprotease inhibitors, triazolopyrimidine (a PDGF antagonist), nitric oxide or nitric oxide donors, super oxide dismutases, super oxide dismutase mimetic, 4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl (4-amino-TEMPO), estradiol, anticancer agents, dietary supplements such as various vitamins, and a combination thereof. Examples of such cytostatic substance include angiopeptin, angiotensin converting enzyme inhibitors such as captopril (e.g. Capoten� and Capozide� from Bristol-Myers Squibb Co., Stamford, Conn.), cilazapril or lisinopril (e.g. Prinivil� and Prinzide� from Merck & Co., Inc., Whitehouse Station, N.J.). An example of an antiallergic agent is permirolast potassium. Other therapeutic substances or agents which may be appropriate include alpha-interferon, and genetically engineered epithelial cells. The foregoing substances are listed by way of example and are not meant to be limiting.
Other bioactive agents may include antiinfectives such as antiviral agents; analgesics and analgesic combinations; anorexics; antihelmintics; antiarthritics, antiasthmatic agents; anticonvulsants; antidepressants; antidiuretic agents; antidiarrheals; antihistamines; antimigrain preparations; antinauseants; antiparkinsonism drugs; antipruritics; antipsychotics; antipyretics; antispasmodics; anticholinergics; sympathomimetics; xanthine derivatives; cardiovascular preparations including calcium channel blockers and beta-blockers such as pindolol and antiarrhythmics; antihypertensives; diuretics; vasodilators including general coronary; peripheral and cerebral; central nervous system stimulants; cough and cold preparations, including decongestants; hypnotics; immunosuppressives; muscle relaxants; parasympatholytics; psychostimulants; sedatives; tranquilizers; naturally derived or genetically engineered lipoproteins; and restenoic reducing agents. Other active agents which are currently available or that may be developed in the future are equally applicable.
The examples set forth below are for illustrative purposes only and are in no way meant to limit the invention. The following examples are given to aid in understanding the invention, but it is to be understood that the invention is not limited to the particular materials or procedures of examples.
In this example, 5 g glycolide (GA), 15 g caprolactone (CL), and 5 g L-lactide (LLA) as monomers, 0.056 mL stannous octoate as catalyst, 0.15 mL dodecanol as initiator and 50 ml xylene as solvent are used.
In this example, 5 g glycolide (GA), 15 g caprolactone (CL), and 5 g L-lactide (LLA) as monomers, 0.056 mL stannous octoate as catalyst, 0.05 mL ethylene glycol as initiator and 50 ml xylene as solvent are used.
The coating solution is prepared by mixing copolymer with drug in a solvent. The copolymer can be P(GA-co-CL)-b-PLLA, P(GA-co-TMC)-b-PLLA, PLLA-b-P(GA-co-CL)-b-PLLA, or PLLA-b-P(GA-co-TMC)-b-PLLA. Everolimus, Sirolimus, Paclitaxel, or their derivatives could be used as drug, and acetone, dimethylene chloroform, or their mixtures could be used as solvent. The weight ratio of copolymer to drug is in the range of 0.1:1 to 10:1, and the weight percent of copolymer in the solution is in the range of 0.1-4 wt %. The coating layer is prepared through spray/dip/drop coating of solution on stent backbone.
While particular embodiments of the present invention have been shown and described, it will be obvious to those skilled in the art that changes and modifications can be made without departing from this invention in its broader aspects. Therefore, the appended claims are to encompass within their scope all such changes and modifications as fall within the true spirit and scope of this invention.
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Jul. 10 (GIN) – As preparations get underway for the July 18th, 94th birthday of former president Nelson Mandela, hurt and angry feelings were expressed by Winnie Madikizela-Mandela who claimed 'shabby treatment' by the ruling ANC party.
The Mail & Guardian newspaper reported that Mrs. Madikizela-Mandela accused the ANC of disrespecting the Mandela family and of "never having any interest in celebrating Tata's (Mandela's) birthday except to gate crash on the family's arrangements."