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Local Veterinarians in Your Area
1015 Montauk Hwy, Copiague, NY 11726
Southgate Animal Hospital is a full-service hospital that has served our community since 1991. We are dedicated to providing you and your furry family member the best customer service and the best quality care. Southgate Animal Hospital is accredited by the American Animal Hospital Association,
3296 Merrick Rd, Wantagh, NY 11793
Services The South Shore Animal Hospital provides a full range of outpatient and hospital care. These services include x-ray capabilities, surgery, E.K.G., gas anesthesia and dental care. Emergencies The South Shore Animal Hospital assures 24 hour emergency coverage. Coverage will be
308 Deer Park Rd, Dix Hills, NY 11746
Welcome to Comprehensive Animal Health Care Center! Alberto G. Gil D.V.M is a conventionally-trained veterinarian who has been practicing medicine for over 30 years in Latin America, United States, and Europe. In his constant search for knowledge, Dr. Gil was involved in extensive cattle-research
6320 Route 25A, East Norwich, NY 11732
We're more than an animal hospital! We're the place where pet parents know they can bring their pets for superb veterinary care that sets new standards for quality and kindness. For pets and pet parents alike, a trip to our clinic is an opportunity to see how our neighborly, welcoming staff cares
64 Pine Hollow Road, Oyster Bay, NY 11771
Welcome to Oyster Bay Animal Hospital Oyster Bay Animal Hospital provides quality veterinary care for dogs, cats, pocket pets and exotics in Oyster Bay, New York and the surrounding communities. We treat pets with the finest medical care in a loving and compassionate environment. make an
229 Wall St, Huntington, NY 11743
Vaccination Clinic available on Saturdays by appointment. Sunday hours are available by appointment only
61 Sunrise Hwy, Merrick, NY 11566
Welcome to Merrick Veterinary Group! Merrick Veterinary Group is a full-service facility with state-of-the-art equipment and technology which allows us to offer advanced medical, surgical and dental care. Merrick Veterinary Group is a companion animal and exotic medicine practice committed toview deal
521 Sunrise Hwy, West Islip, NY 11795
Here at Sunrise Vet Group, we are dedicated to ensuring that your pet lives a longer, healthier life. Our experienced staff works extremely hard to provide you and your pet with the best in quality medicine and care. We offer every service, from wellness consultations to intricate surgery! Our
3095 East Jericho Tpke, East Northport, NY 11731
Commack Animal Hospital in East Northport, NY is a full service companion animal hospital. It is our responsibility not only to offer the best possible care for your pet, but to explain our recommendations so that you can make intelligent informed decisions. Our goal is to practice the highest
1798 Merrick Road, Merrick, NY 11566
Welcome to Companions Animal Hospital! Companions Animal Hospital is dedicated to enriching and prolonging the bond you share with your animal companions. We believe excellent veterinary care, in conjunction with thorough communication and education, allows our companions to live longer,view deal

subset: commoncrawl


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TODAY'S MUST SEE: Kids react to a realistic Barbie doll
The Lammily doll wants to show children that average is beautiful.
Arkansas Flu Shot Clinic Dates Being Set
Craighead County Flu Shot Date "To Be Determined"
Review Your Ballot Before You Vote
A lot of people have asked if there is a way to see your ballot before you go to the polls. Here's the way!
Miracle League Field Opens In Jonesboro
New Field Officially Dedicated Saturday


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Originally written on NESN.com | Last updated 11/13/14
NESN.com staff will pick the two or three best Amica Coverage Plays of the previous week for games played from Friday night to Thursday night. Voting will begin every Friday morning and conclude on Monday. The Bruins did not have many bright spots in their 3-1 loss to the Flyers on Saturday. They fell behind for the fourth straight game, this time 2-0, and were stonewalled by Philadelphia goalie Ilya Bryzgalov, who made 33 saves. Nathan Horton provided the lone highlight for the Bruins, and not just by scoring their only goal. A deeper analysis of the play showed how Horton kept working to score on a rebound after making a fundamental pass to Dennis Seidenberg to put the Bruins in position to score. Check out the Amica Coverage Cam play breakdown in the video above.
PLAYERS: Nathan Horton, Ilya Bryzgalov, Dennis Seidenberg
TEAMS: Boston Bruins, Philadelphia Flyers
TEAMS: Boston Bruins, Philadelphia Flyers
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Cool new life science products from Techne
ACHEMA 2009 saw the launch of two innovative sample-cooling products from Techne: the N° ICE is an electronic ice bucket containing ceramic-coated beads and the BL°CKICE cools tubes held in two Dri-Block® inserts. Both the N° ICE and BL°CKICE are ideal for incubating samples for short or long periods at temperatures down to 0°C - no more tubes floating in boxes of melting wet ice!
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Heyyyy.....I've got an idea......I'll include some tape and a timer, all you need to do is find out where your ex is going to sleep; you can solve several problems at once!!
Seriously, I know now much that must have hurt, but in the end, you got the better end of the deal. Imagine how bad it would be if you would have found out about his.....well.......shall we say 'lack of moral character' after your relationship would have gone even deeper.
Sometimes a little pain now is better than a lot more later on.
This'll sound completely weird, but believe it or not, it actually works.
You know how you get the brain freeze if you eat a milkshake too fast........put a dash of pepper in it. You can't taste the pepper, and it'll prevent the brain freeze. Works with ice cream too.
Im not one for Violence but that guy needs a good Smackin!!! Only a total jerk*** Would use your mothers friendship to be around you.
You've got a LOT going for you, it may take some time, but 'the one' is out there....somewhere.....
I'm going to bed, I'm really tired and my back still aches. Good luck with everything going on with your ex, Amanda! Nanners, everyone!


text: 'You Are My Favourite Husband' Card by I am Nat £3$5.72€3.95$5.02 10 customer reviews(10) In stock £0.95$1.81€1.25$1.59 mainland UK delivery - Order now and receive this item on or before Wednesday 3 December £0.95$1.81€1.25$1.59 mainland UK deliveryEstimated delivery: 2-3 days £7.90$15.07€10.40$13.22 Express Next Day 1pm - Order now and receive this item on or before Tuesday 2 December Express delivery available International delivery available quantity by I am Nat Location: North Yorkshire, GB read seller's profile see seller's complete range more items from this seller 'Raison D'etre' Anniversary Card £3$5.72€3.95$5.02 'I'm Me With You' Card £3$5.72€3.95$5.02 'You Are My Favourite' Card £3$5.72€3.95$5.02 Alice In Wonderland 'Bonkers' Poster Print £12.50$23.84€16.45$20.92 new Alice In Wonderland Colour 'Bonkers' Poste... £12.50$23.84€16.45$20.92 Alice In Wonderland Poster Print £12.50$23.84€16.45$20.92 view all you may also like PRODUCT DETAILS CUSTOMER REVIEWS DELIVERY RETURNS Made in Britain eco-friendly ask seller a question Simple typographic card with a cheeky edge to it. Tell your husband he is your favourite with this cheeky vintage inspored card, which reads 'You are my favourite husband'. The perfect card for anniversaries, birthdays, valentine's day or even just because. Sure to put a smile on the face of all husbands! This card is left blank inside for your own personal message. made from: 300gsm Hammered card, supplied with a white envelope. dimensions: 14.5cm x 14.5cm product code: 178573 10 customer reviews Sat 08 Nov 2014 No comment supplied. Fri 24 Oct 2014 Perfect card & quick delivery. Wed 10 Sep 2014 No comment supplied. Wed 21 May 2014 A quote I often say to my husband, for the response 'I thought I was your only husband' ha ha... Nice card for our first anniversary x Tue 18 Feb 2014 Good product Mon 01 Jul 2013 Good quality card Wed 12 Jun 2013 Perfect card! Fri 26 Apr 2013 Lovely quality card. Sat 01 Sep 2012 Unique card. Really fast confirmation of order from the seller and very quick dispatch. Thank you. Fri 10 Aug 2012 A lovely card for that 'no particular reason' reason! see all customer reviews hide some customer reviews read about our product rating system ratings guide trusted independent customer feedbackforum excellent bad good poor This product is dispatched to you by I am Nat. MAINLAND UK order now and receive this item on or before price Standard Delivery Wednesday 3 December £0.95$1.81€1.25$1.59 Express Next Day 1pm Tuesday 2 December £7.90$15.07€10.40$13.22 NON-MAINLAND UK estimated delivery price Highlands & Islands of Scotland 2-5 daysfrom dispatch £0.95$1.81€1.25$1.59 Northern Ireland 2-5 daysfrom dispatch £0.95$1.81€1.25$1.59 Other UK Islands 2-5 daysfrom dispatch £2.95$5.62€3.88$4.93 INTERNATIONAL DELIVERY estimated delivery price Western Europe 2-5 daysfrom dispatch £2.45$4.67€3.22$4.10 Rest of Europe 5-10 daysfrom dispatch £2.45$4.67€3.22$4.10 USA & Canada 5-10 daysfrom dispatch £2.45$4.67€3.22$4.10 Far East & Australasia 5-10 daysfrom dispatch £2.45$4.67€3.22$4.10 Rest of the world 5-14 daysfrom dispatch £2.45$4.67€3.22$4.10 You have 28 days, from receipt of cancellable goods, to notify the seller if you wish to cancel your order or exchange an item. Please note: goods that are personalised, bespoke or made-to-order to your specific requirements, perishable products and personal items sold with a hygiene seal (cosmetics, underwear) in instances where the seal is broken are non-refundable, unless faulty. Read more about our returns policy.Should you choose to return or exchange your order you will need to deliver the item(s) to the UK, where this seller is based. I am Nat's return policy


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INFM 603: Information Technology and Organizational Context Session 2: HTML and CSS (And Networking, Computing Tradeoffs) Jimmy Lin The iSchool University of Maryland Thursday, September 13, 2012 Ways to characterize computing ¢ How big? ¢ How fast? ¢ How reliable? Computing is fundamentally about tradeoffs! Example 1: Multi-Core Source: Wikipedia (Moore's Law) Trends in Computing: #1 2.7 GHz in 2012 Huh? 3.4 GHz in 2003 Source: Wikipedia (Moore's Law) What's big shift? ¢ From single to multiple cores: l Increasing speed of single processor reached point of diminishing returns l Solution: put more cores on a processor! ¢ Important issues: l Power l Cool l Parallelism Example 2: Caching Typical Access Time: 100 ns Source: Wikipedia Typical Access Time: 10 ms (10,000x slower than RAM!!!) Source: Wikipedia Pick two ¢ Speed ¢ Capacity ¢ Cost RAM: small, expensive, fast Hard drives: big, cheap, slow Best of both worlds? cheap, fast, and big Think about your bookshelf and the library… Caching ¢ Idea: move data you're going to use from slow memory into fast memory l Slow memory is cheap so you can buy lots of it l Caching gives you the illusion of having lots of fast memory ¢ Physical analogy? ¢ How do we know what data to cache? l Spatial locality: If the system fetched x, it is likely to fetch data located near x (Why?) l Temporal locality: If the system fetched x, it is likely to fetch x again (Why?) Example 3: Replication Characterizing Reliability "Nines" Availability Downtime (per year) One nine 90% 36.5 d Two nines 99% 3.65 d Three nines 99.9% 8.76 h Four nines 99.99% 52.56 m Five nines 99.999% 5.256 m Six nines 99.9999% 31.536 s How do you ensure reliability? ¢ Keep multiple copies: l On different machines l On different machines far apart ¢ What are the challenges with this? l Synchronous vs. Asynchronous l Active-Active vs. Active-Passive l… Facebook architecture (circa 2008) Source: Technology Review Networking Source: http://www.flickr.com/photos/fusedforces/4324320625/ Internet Web ¢ Internet = collection of global networks ¢ Web = particular way of accessing information on the Internet l Uses the HTTP protocol ¢ Other ways of using the Internet l Usenet l FTP l email (SMTP, POP, IMAP, etc.) l Internet Relay Chat Intranets Intranet Gateways Intranet What are firewalls? Why can't you do certain things behind firewalls? Intranets Problem: How do you securely connect separate networks? Public Internet Intranet "leased line" Intranet VPN = Virtual Private Network a secure private network over the public Internet Source: http://www.extremetech.com/computing/96827-the-secret-world-of-submarine-cables Foundations ¢ Basic protocols for the Internet: l TCP/IP (Transmission Control Protocol/Internet Protocol): basis for communication l DNS (Domain Name Service): basis for naming computers on the network ¢ Protocol for the Web: l HTTP (HyperText Transfer Protocol): protocol for transferring Web pages IP Address ¢ Every computer on the Internet is identified by a address ¢ IP address = 32 bit number, divided into four "octets" l Example: go in your browser and type "http://184.108.40.206/" Are there enough IP addresses to go around? What is the difference between static and dynamic IP? Packet Routing (TCP/IP) 184.108.40.206 18.104.22.168 22.214.171.124 220.127.116.11 18.104.22.168 18.104.22.168 (Much simplified) Routing table for 22.214.171.124 Destination Next Hop 52.55.*.* 184.108.40.206 18.1.*.* 22.214.171.124/126.96.36.199 4.*.*.* 184.108.40.206 … Domain Name Service (DNS) ¢ Domain names improve usability l Easier to remember than IP addresses l DNS provides a lookup service ¢ Each name server knows one level of names l "Top level" name server knows .edu, .com, .mil, … l .edu name server knows umd, mit, stanford, … l .umd.edu name server knows ischool, wam, … Demo ¢ Play with various utilities at l http://network-tools.com/ l http://www.yougetsignal.com/tools/visual-tracert/ l http://en.dnstools.ch/visual-traceroute.html HyperText Transfer Protocol ¢ Send request GET /path/file.html HTTP/1.0 From: email@example.com User-Agent: HTTPTool/1.0 ¢ Server response HTTP/1.0 200 OK Date: Fri, 31 Dec 1999 23:59:59 GMT Content-Type: text/html Content-Length: 1354
Happy New Millennium!
 …   Tell me what happens… ¢ From the moment you click on "check messages" to the moment you start reading your email ¢ From the moment you click "send" to the moment the other party receives the email ¢ From the moment you type a URL and hit "enter" to the moment you see the Web page Tables Source: Wikipedia (Table) Tables

  eenie 	 mennie 	  miney

  mo 	 catch 	  a tiger

  by 	 the 	  toe

 CSS Source: Wikipedia (Waterfall) What's a Document? ¢ Content ¢ Structure ¢ Appearance ¢ Behavior CSS: Cascading Style Sheets ¢ Separating content and structure from appearance ¢ Rules for defining styles "cascade" from broad to narrow: l Browser default l External style sheet l Internal style sheet l Inline style Basics of CSS ¢ Basic syntax: selector {property: value} HTML tag you want to modify… The property you want to change… The value you want the property to take ¢ Example: p { text-align: center; color: black; font-family: arial } Causes l Font to be center-aligned l Font to be Arial and black Different Ways for Using CSS ¢ Inline style: l Causes only the tag to have the desired properties
…
 ¢ Internal stylesheet: l Causes all tags to have the desired properties … …
…
 … Customizing Classes ¢ Ability to define customized styles for standard HTML tags: … …
…

…
 … External Style Sheets ¢ Store formatting metadata in a separate file mystyle.css p.style1 { font-family:arial; color:blue} p.style2 { font-family:serif; color:red} … … <link rel="stylesheet" href="mystyle.css" type="text/css" />
…

…
 … Why Use CSS? ¢ What are the advantages of CSS? ¢ Why have three separate ways of using styles?


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Our sales professional is Doug B. He blended our needs as a family with the needs/ requests of the primary drivers with ease. The purchase of our 2013 X3 was enjoyable. His communication was spot on, and always asked if he could go "the extra mile" to benefit us. Doug made arranging the delivery experience in Spartanburg, SC seamless and memorable. This is the optimal way to purchase a new vehicle from BMW. The factory delivery experience is HIGHLY recommended! Overall, we had a quality purchase experience and would recommend this to others.
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After 9.75 years my landlord is claiming I never paid the last month rent deposit. I have contacted the bank and they are in the process of mailing the canceled checks. The landlord has posted a handwritten eviction notice on my door. She is demanding I move by November 30. She is holding $1700 is security. She wrote me a letter today that states I am trying to cheat her. I am scared as I have a daughter who is absolutely frightened. I am searching for a safe place to move to get away from her harassing. I have gone to the police to report the harassment, but they told me to go to small claims. They also told me that the eviction notice was not legal. What do I do?
You need a landlord-tenant attorney. If you have proof of payment then you will probably win if she tries to evict you. At this point, 9 years later, you are probably on a month-to-month tenancy if you pay your rent on a monthly basis. The landlord can choose to terminate the lease by giving you fifteen days notice. She would then have to file a law suit in county court to evict you.
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LEE COUNTY, Fla.- Anger and accusations today as Lee County school leaders vote to opt back in to state mandated testing. The 3-2 vote to opt out last week changed to a 3-2 vote in the other direction today, when board member Mary Fischer rescinded her vote.
"It is not easy to sit up here and say I want to change my mind," said Fischer. "The kids have been my life's work. That is why I am calling for a reconsideration."
The meeting started at 8:30am which upsetted many people, because they said others were at work and could not attend. The new vote disappointed some, and made others happy.
"I think this is a political game and our children are pawns." Chris Patricca has three children in the Lee County School District and feels Tuesday's vote to return to state mandated testing is a victory.
"I think testing is absolutely necessary to gauge our students mastery of the standards," she said.
She's one of more than 100 people gathered at school district headquarters Tuesday morning. Some parents spoke, saying they didn't like state mandated testing, but wanted a plan in place before the district makes any decision to opt out.
Cape Coral's Mayor Marni Sawicki was one of them.
"Let's take a look at the whole situation, go back to finding a plan and moving forward. I would completely be supportive of that," Mayor Sawicki said.
Others who vigorously supported the districts original decision to opt out of high stakes testing also had a lot to say. "The very real damage of allowing high stakes testing to continue far outweigh the unlikely consequences of any state actions," said one Lee County resident.
Some even called for the resignation of Superintendent Dr Nancy Graham and board member Mary Fischer.
"Dr. Graham seems to be doing a lot of complaining. She needs to get to work or she needs to go," said one speaker.
"It was 8:30 in the morning when this meeting started, over a three day weekend, we packed the house. Again with red t-shirts. I don't know what else we can do to be heard. they don't care. This is absolute tyranny in this community," said Lori Cohn.
Those in the red shirts vowed they would not stop speaking out, and will continue to push the school district to opt out of high-stakes testing in the future.


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Tag: Os10.8.3
OS X Mountain Lion v10.8.3, Security Update 2013-001 now available
Apple has released OS X Mountain Lion 10.8.3 and the first security update of 2013. The update includes a number of good improvements including: The ability to redeem iTunes gift cards in the Mac App Store using the built-in camera on a Mac. Boot Camp support for installing Windows 8 and...
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- World Cup Ignored 11
Cabella call him up to the national side, this was most likely his last chance. Filipe Luis : Beaten out by his opposite of the opposite team in the same city, Filipe Luis' position ... final, but was a contrast of bitterweet between the two. Felepe Luis is a player of attacking flair ...
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at the hospital. Upon regaining consciousness, she began to speak to her husband, journalist Luis Grace ...
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Brazil have graced the World Cup with some of the best players and most dazzling performances ever seen ... by Menezes had already begun to whisper that former Brazil coach Luis Felipe Scolari should be installed ... and there was no sign of an inferiority complex as Luis Fernando Tena's side made an astonishing start. Just 30 ...
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condition worsening, her husband-journalist Luis Grace insisted on admitting her into the hospital after ...
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"feelers" about a possible arrangement to allow Estrada a graceful exit, and vowed to facilitate ... popularity sunk after a former friend, provincial governor Luis Singson, accused him last month of accepting ...
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Provided are rapidly bioavailable solid oral dosage forms of acute pain medications, and moisture resistant packaging that enables the formulation of such rapidly bioavailable dosage forms.
1. A method of packaging a rapidly bioavailable diclofenac potassium tablet comprising:
a) formulating a 50 mg. diclofenac potassium tablet dosage form for rapid bioavailability, in a formulation comprising:
i) at least 20 wt. % of one or more alkali metal carbonate or bicarbonate salt excipients that are freely soluble in water, and
ii) from about 30 to about 80 wt % of a hygroscopic diluent and said one or more freely soluble diluents at a weight ratio of from about 1:20 to about 5:1, wherein said hygroscopic diluent absorbs greater than about 0.5 wt. % water within a twenty four hour period in a humidity chamber maintained at 60% relative humidity ("RH") and 25° C.; and
b) packaging said dosage form in a moisture resistant bottle that prevents said dosage form from absorbing more than 4 wt. % moisture in three months when stored at 40° C. and 75% relative humidity.
2. The method of
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The present invention concerns rapidly bioavailable solid oral dosage forms and moisture resistant packaging that enables the formulation of such dosage forms. The invention is particularly concerned with packaging systems for acute pain medications.
The bioavailability of pharmaceutical products is a critical concern in rational drug design. The pharmacokinetics of a drug, which measure the time it takes a drug to become bioavailable and its concentration profile in serum over time, can have a significant effect on the effectiveness of a drug, as well as its safety. Pharmacokinetics are of particular concern for drugs that require an immediate onset of action, such as drugs used in the treatment of acute pain.
Various factors can influence the time it takes for a drug to become bioavailable in therapeutically effective concentrations. For orally administered solid dosage forms, some of the most important parameters include the disintegration/dissolution time of the drug, the stability and solubility of the molecule in the gastrointestinal tract, and first pass metabolism, to mention just a few. For some drugs such as potassium diclofenac the pH of the formulation can also affect its bioavailability. For example, it is known that diclofenac potassium has a tendency to precipitate in an acidic environment, thereby making it less bioavailable. This problem is highlighted in bioavailability studies of Cataflam, a commercially marketed form of diclofenac potassium, which exhibits two concentration peaks in the bloodstream when orally ingested.
When rapid bioavailability is desired, preferred modes of administration include parenteral, inhalation, mucosal and buccal administration. Tablets and capsules are generally available only in immediate release, extended release, and delayed release formats, and are not typically employed when rapid bioavailability is desired because of the time it takes for the dosage form to dissolve, and the resulting delay in gastrointestinal absorption. A novel delivery system for orally delivering diclofenac in a rapidly bioavailable tablet has been proposed in PCT/EP97/02709 (published as WO 97/44023), but solid oral dosage forms based on this type of platform are clearly the exception and not the rule.
It is an object of the present invention to increase the rate of bioavailability of solid oral dosage forms, such as tablets and capsules.
Another object of the present invention is to increase the bioavailability of acute pain medications.
It is another object to provide packaging for rapidly bioavailable solid oral dosage forms that preserves and enhances their bioavailability, stability and physical handling properties.
It has unexpectedly been discovered that diclofofenac potassium tablets, particularly those formulated for rapid disintegration and dissolution, can be made to disintegrate and dissolve faster by limiting their moisture uptake during storage, and allowing them to become harder over time. Whereas one would normally expect a tablet to disintegrate faster as it softens, the inventors have discovered that diclofenac potassium tablets disintegrate slower when the tablet softens, and that the tablet will not become softer if it is protected from moisture. In other words, the inventors have discovered that one can make diclofenac potassium tablets disintegrate faster, and hence be more rapidly bioavailable, simply by preventing them from absorbing moisture during storage. These results are counterintuitive and support the patentability of the present invention.
Therefore, in one embodiment the invention provides a method of packaging a rapidly bioavailable diclofenac potassium tablet comprising: (a) formulating a potassium diclofenac tablet for rapid bioavailability; and (b) packaging said tablet in a moisture resistant bottle that prevents said tablet from absorbing more than 2.0 wt. % moisture in three months when stored at 40° C. and 75% relative humidity. In another embodiment, the invention provides a method for treating a patient suffering from acute pain by administering the tablets packaged according to the present invention. Tablets are formulated for rapid bioavailability in the sense that they are specially formulated to quickly disintegrate or dissolve rapidly when ingested in the stomach, for example in less than ten or even five minutes.
Additional advantages of the invention will be set forth in part in the description which follows, and in part will be obvious from the description, or may be learned by practice of the invention. The advantages of the invention will be realized and attained by means of the elements and combinations particularly pointed out in the appended claims. It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention, as claimed.
As used in the specification and claims, the singular forms a, an and the include plural references unless the context clearly dictates otherwise. For example, the term a pharmaceutical excipient may refer to one or more pharmaceutical excipients for use in the presently disclosed formulations and methods.
USP means the United States Pharmacopeia and National Formulary (USP 28-NF 23). Rockville, Md.: United States Pharmacopeia Convention; 2004, unless stated to the contrary. USP 28<701> refers to physical test 701, disintegration, contained on pages 2411-2412 of the USP. USP 28 <711> refers to physical test 711, dissolution, contained on pages 2412-2414 of the USP.
A dosage form, as used herein, refers to a formulation that is ready for administration to a subject. As used herein, it specifically refers to solid dosage forms, including, but not limited to, tablets, capsules and powders. Tablets are most preferably employed, though it will be understood that other solid oral dosage forms can also benefit from the teachings of the present invention. An "intact" dosage form refers to a dosage form which is ingested in the form it is provided. Intact dosage forms are therefore to be distinguished from orally disintegrating tablets which disintegrate in the mouth before being ingested, or effervescent tablets which are dissolved in water before being ingested. In preferred embodiments of this invention, the dosage form is a tablet, and the tablets are ingested in an intact form.
Cmax refers to the maximum plasma concentration of a drug following oral administration of the solid oral dosage form to patients. Normalized Cmax refers to the value obtained by dividing Cmax into the dosage strength of the solid oral dosage form.
AUC refers to the area under the curve that tracks the plasma concentration (ng/ml) of a drug over a given time following the oral administration of the solid oral dosage form to patients. AUC can be measured from 0 to 12 hours or from 0 to 24 hrs following the administration and in these cases are referred to as AUC ((0-12) )or AUC ((0-24)), respectively.
Normalized AUC is obtained by dividing the AUC into the dosage strength of the solid oral dosage form of the drug. For example, if the AUC ((0-12)) is 160 hr·ng/ml following the oral administration of a solid oral dosage form containing 200 mg of active ingredient, the normalized AUC ((0-12) )is 0.8 hr·ng/ml/mg.
An excipient is considered "freely soluble" in the context of this application if the excipient meets the requirements for either "freely soluble" or "very soluble" excipients set forth in the United States Pharmacopeia. Therefore, an excipient that is "freely soluble" in water is an excipient for which 10 or fewer parts of water are required to dissolve one part of the excipient material at 20° C.
Diclofenac is chemically described as [(2,6-dichloro-anilino)-2-phenyl]-2-acetic acid, and is represented by the following chemical structure:
Acute pain conditions include pain that is temporary or passing, in contrast to chronic pain that is recurring or constant. Acute pain conditions thus include pain deriving from soft tissue disorders such as sprains and strains, soft tissue lascerations, migraine attacks, and other painful conditions such as renal colic, acute gout, dysmenorrhoea, and following invasive surgical procedures. While the invention is particularly useful in the treatment of acute pain, it will also be understood that the compositions of the present invention are also useful in chronic pain conditions. Examples of chronic pain conditions include rheumatoid arthritis, osteoarthritis, and ankylosing spondylitis; and periarticular disorders such as bursitis and tendonitis.
Reducing Moisture Uptake to Improved Bioavailability
As discussed above, the invention relates to moisture resistant packaging, and the use of moisture resistant packaging to decrease the disintegration/dissolution time of diclofenac potassium dosage forms. In one embodiment the invention provides a method of packaging a rapidly bioavailable diclofenac potassium tablet comprising: (a) formulating a solid oral potassium diclofenac dosage form (preferably a tablet) for rapid bioavailability; and (b) packaging said dosage form in a moisture resistant bottle that prevents said dosage form from absorbing more than 4.0 3.0, 2.0 or even 1.0 wt. % moisture in three months when stored at 40° C. and 75% relative humidity. In another embodiment the invention relates to methods of using rapidly bioavailable diclofenac potassium dosage forms that are packaged in moisture resistant bottles, and provides a method of treating acute pain comprising: (a) providing a rapidly bioavailable solid oral potassium diclofenac dosage form (preferably a tablet) in a moisture resistant bottle that prevents said dosage form from absorbing more than 2.0 wt. % moisture in three months when stored at 40° C. and 75% relative humidity; and (b) administering said diclofenac potassium dosage form to a patient suffering from acute pain.
Various methods can be used to ensure that the tablets do not absorb more moisture than is called for by the present invention. A hermetic seal on the bottle is perhaps most important, which could constitute nothing more than a foil or other laminar seal at the opening to the bottle. A dessicant pouch, such as a silica gel pouch, may also be used for absorbing any moisture that does enter the bottle.
The dosage forms are rapidly bioavailable in the sense that they are specially formulated to disintegrate/dissolve quickly when ingested into the stomach. Numerous means are available for promoting the disintegration or dissolution of diclofenac tablets or capsules, including, for example, the shell used for the capsule, formulation excipients such as disintegrants, pH buffers, effervescing agents, freely soluble excipients, hygroscopic excipients, surfactants that promote the disintegration and dissolution of the dosage form and the active molecule, and counterions of the drug molecule. The dosage forms of the present invention are typically characterized by an inverse relationship between disintegration rate and moisture uptake. The hardness of the tablets is typically greater than about 4.1 kp, and more typically greater than about 6.0 or 8.0 kp.
Disintegration times for the dosage forms of the present invention, when tested according to USP 28 <701>, are preferably less than about 20 minutes, 15 minutes, 10 minutes, 5 minutes, or even 4 minutes, and greater than about 1, 2 or 3 minutes, most preferably from about 3 to about 5 minutes. Dissolution times for the dosage forms of the present invention, when tested according to USP 28 <711>, based on the time it takes to dissolve 90 or 95 wt. % of the drug substance, are preferably less than about 20 minutes, 15 minutes, 10 minutes, 5 minutes, or even 3 minutes, and greater than about 1 or 2 minutes. In a preferred embodiment, the dissolution profile for the dosage forms of the present invention is in accordance with the following specification: not less than 85, 90 or 95% dissolved after 15 minutes in simulated intestinal fluid (e.g. water) at pH=6.8
Mean tmax attained by the dosage forms of the present invention is preferably less than about 40 minutes, 35 minutes, 30 minutes, 25 minutes or 20 minutes, and greater than about 5 minutes, 10 minutes or 15 minutes. Mean tmax is preferably from about from about 5 to about 30 minutes, from about 10 to about 30 minutes, or from about 13 to about 27 minutes. The corresponding coefficient of variation for most diclofenac tablets is normally in the range of 70-90%, which means that the Tmax is strongly variable and dependent on the physical characteristics of the patient (Physicians' Desk Reference, 52 edition, 1998, pag. 1831)). In contrast, the inter-subject coefficient of variability for said tmax for dosage forms of the present invention is preferably less than about 80, 75, 60, 50, 49, 46, 40, 35, 30% or 25%.
Mean Cmax attained by the formulations of the present invention, for a 50 mg. formulation, is preferably greater than about 1400 ng/ml (0.028 liter−1), 1500 ng/ml (0.03 liter−1), 1600 ng/ml (0.032 liters−1) or 1700 ng/ml (0.034 liter−1), and less than about 2500 ng/ml (0.05 liter−1) or 2300 ng/ml (0.046 liter−1). A preferred range is 1500-2500, 1700-2500, or 1700-2300 ng/ml for a 50 mg. formulation. The inter-subject coefficient of variability for said Cmax preferably is less than about 70, 60, 50, 45 or 40%. In contrast to other commercially marketed diclofenac formulations, the formulations of the present invention preferably display only one meaningful peak blood concentration after ingestion. Compare
Preferred Cmax and tmax ranges for various dosage forms of the invention are set forth below in Table A:
In one embodiment the rapid bioavailability is achieved by incorporating in the dosage form means for generating a gaseous and alkaline environment when orally ingested into the stomach. Suitable means for generating a gaseous and alkaline environment that is not harmful to the gastrointestinal mucosa include, but are not limited to, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, calcium carbonate, magnesium carbonate, sodium glycine carbonate, disodium hydrogen phosphate, sodium dihydrogen phosphate, and mixtures thereof. Suitable gas generating means are not limited to those which are based upon a reaction which forms carbon dioxide. Reactants which evolve oxygen or other gases and which are safe for human consumption are also considered within the scope of the present invention.
The dosage form also preferably includes a hygroscopic excipient which may double as the means for generating an alkaline and gaseous environment. Products that at relative humidity of 80% (RH=80%) and 25° C. demonstrate low water absorption ability (lower than 1% during 24 hrs) have a hygroscopic point below 80% (j<80% RH) and are not considered hygroscopic within the meaning of this invention. A hygroscopic excipient could thus have the ability to absorb greater than about 1 wt. %, 3 wt. %, 5 wt. % or 7 wt. % moisture within a twenty four hour period in a humidity chamber maintained at 80% RH and 25° C. Alternatively, a hygroscopic excipient could be defined as an excipient that is able to absorb greater than about 0.75 wt. %, 1 wt. %, 2 wt. %, 3 wt. % or 4 wt. % moisture within a twenty four hour period in a humidity chamber maintained at 60% RH and 25° C. Various hygroscopic excipients could be used in practicing the present invention, including various water-soluble hygroscopic polyhydroxy compounds or esters thereof such as glycerol and its mono- and diesters derived from low molecular weight carboxylic acids, e.g., monoacetin and diacetin (respectively, glyceryl monoacetate and glyceryl diacetate), ethylene glycol, diethylene glycol, triethylene glycol, 1,3-propanediol, trimethylolethane, trimethylolpropane, pentaerythritol, sorbitol, and the like. Other examples of hygroscopic or water-swellable materials include pharmaceutically acceptable disintegrants such as crosslinked polyvinylpyrrolidone, starch NF, and hygroscopic. In a preferred embodiment the hygroscopic excipient is potassium bicarbonate or sodium bicarbonate.
The means for generating a gaseous and alkaline environment and/or hygroscopic excipients are typically employed in a weight ratio relative to the diclofenac of greater than about 1:5, 2:5, 2:1, 3:1 or 5:1. If desired, an upper limit on the buffer: diclofenac ratio can be placed at about 20:1, 10:1, 5:1, 1:1, 4:5 or 3:5. Ranges can be selected from any two of the foregoing values that are mathematically possible. In a preferred embodiment, the buffer:diclofenac weight ratio ranges from about 1:5 to about 4:5. As a total percentage of the dosage form, the means for generating a gaseous and alkaline environment preferably makes up greater than about 5, 7 or 9 wt. % of the dosage form formulation, and less than about 25, 20 or 15 wt. % of the formulation. The means preferably yields a pH greater than about 7.0, 7.5, 7.8 or 8.0, and less than about 9.2, 9.0, 8.8 or 8.5 when the dosage form is mixed with 50 ml of water at 25 degrees Celsius. Alternatively, the means preferably yields a pH greater than about 6.8, 7.0, 7.2, or 7.5, and less than about 8.8, 8.5, 8.3 or 8.0 when the dosage form is mixed with 200 ml of water at 25 degrees Celsius.
Alternatively, the dosage form itself can be characterized by its hygroscopicity. In the present invention, dosage forms that at relative humidity of 80% (RH=80%) demonstrate low water absorption ability (lower than 1% during 24 hrs) have a hygroscopic point below 80% (j<80% RH) and are not hygroscopic at normal conditions. A hygroscopic dosage form could thus have the ability to absorb greater than about 1 wt. %, 1.25 wt. %, 1.5 wt. % or 2 wt. % moisture within a twenty four hour period in a humidity chamber maintained at 80% RH and 25° C. Alternatively, a hygroscopic dosage form could be defined as a dosage form that is able to absorb greater than about 0.50 wt. %, 0.75 wt. %, 1 wt. %, 1.25 wt. %, or 1.5 wt. % moisture within a twenty four hour period in a humidity chamber maintained at 60% RH and 25° C.
Tests performed on 50 mg. diclofenac potassium tablets of the present invention maintained at 25° C. and 60% RH over twenty four hours showed an increase in KF (% water) from 1.995% (at time zero) to 3.456% (after 24 hours). Tests performed on 50 mg. diclofenac potassium capsules of the present invention maintained at 25° C. and 60% RH over twenty four hours showed an increase in KF (% water) from 1.905% (at time zero) to 2.93% (after 24 hrs.). The final dosage form will not typically contain greater than about 5 wt. % water, initially or after 1, 2 or 3 years of storage.
The dosage form can also be formulated to be rapidly bioavailable by incorporating at least 20 wt. %, 30 wt. %, 40 wt. %, 50 wt. %, or 60 wt. % of excipients that are freely soluble in water. An excipient is considered freely soluble in the context of this application if 1 part of excipient is soluble in 1-10 parts of water at 20° C. Examples of freely soluble excipients include mannitol, dextrates (i.e. a purified mixture of saccharides resulting from the controlled enzymatic hydrolysis of starch), dextrin, dextrose, fructose, lactilol, lactose anhydrous, sorbitol, sucrose, and compressible sugar. Of these, mannitol and lactilol are particularly preferred due to their beneficial non-hygroscopic properties, which improves their processability and handling during the manufacturing process. In a preferred embodiment the dosage form will comprise from about 30 to about 80 wt. % of the combined hygroscopic diluent and freely soluble diluent, from about 35 to about 75 wt. % of the combined hygroscopic diluent and freely soluble diluent, or from about from about 40 to about 70 wt. % of the combined hygroscopic diluent and freely soluble diluent. In addition, the hygroscopic diluent and freely soluble excipient will preferably be present in a weight ratio of from about 1:20 to about 5:1, from about 1:10 to about 3:1, from about 1:8 to about 1:1, from about 1:8 to about 1:2, or from about 1:4 to about 1:1.
Yet another way to render the dosage forms rapidly bioavailable is to incorporate a surfactant that aids in the solubility of the dosage form, such as sodium lauryl sulfate. Preferred surfactants will have an HLB value of at least 10 or 12, and preferably at least about 14 or 15. An upper bound can also be placed on the HLB of the surfactant, preferably of 60, 50 or 40. In certain preferred embodiments, the HLB value of the surfactant is from about 15 to 60, and in further embodiments the HLB is most preferably from about 20 to about 50. Suitable pharmaceutically-acceptable anionic surfactants include, for example, those containing carboxylate, sulfonate, and sulfate ions. The most common cations associated with these surfactants are sodium, potassium, ammonium and triethanolamine. The chain length of the fatty acids typically range from 12 to 18. Although a large number of alkyl sulfates are available as surfactants, one particularly preferred surfactant is sodium lauryl sulfate, which has an HLB value of about 40. Other suitable wetting agents include glyceryl monooleate, sorbitan ester, docusate sodium, and cetrimide.
A preferred class of acute pain medications for use in the present invention are non-steroidal anti-inflammatory drugs including, among others, fenamic acid derivatives, indene derivatives, and ibufenac derivatives. Csŕky and Barnes in "Cutting's Handbook of Pharmacology," Appleton-Century-Crofts, Norwalk, CN (1984). Fenamic acid derivatives are broadly classified as o-anilino derivatives of benzoic, phenylacetic, and nicotinic acids and are defined by Csŕky and Barnes as including flufenemic acid, mefenamic acid, meclofenamic acid, clonixeril, clonixin, flunixin, and diclofenac, including the pharmaceutically acceptable salts thereof. Indene derivatives generally are acetic acid, propionic acid, and benzoic acid derivatives containing a pyrrole (or a pyrazole, pyrroline or pyrrolidine) ring and are defined by Csŕky and Barnes as including indomethacin, carprofen, etodolac, fendosal, indoprofen, prodolic acid, sermetacin, zidometacin, and zomeprirac, including the pharmaceutically acceptable salts thereof. Compounds not so classified by Csŕky and Barnes but related in being acetic acid, propionic acid, or benzoic acid, derivatives and here so classified include tolmetin, sulinac, cicloprofen, and cinchophen, including the pharmaceutically acceptable salts thereof. Ibufenac derivatives are acetic and propionic acid derivatives bearing a substituted aromatic hydrocarbon ring, such as phenyl or naphthyl, and are defined by Csŕky and Barnes as including iflunisal, fenoprofen, ibuprofen, naproxen, alclofenac, amfenac, cliprofen, fenclofenac, fenclorac, fluprofen, ketoprofen, naproxol, fenbufen, and ibufenac, including the pharmaceutically acceptable salts thereof.
Diclofenac acid and its pharmaceutically acceptable salts are a particularly preferred acute pain medication, especially diclofenac potassium. Other pharmaceutically acceptable salts include those of sodium and other alkali and alkaline earth metals, or salts of organic nature, such as the salts of basic amino acids, such as lysine, arginine and ornithine. In a preferred embodiment, 10-60 mg. or 50 mg. of diclofenac potassium is used in the final dosage form, although other amounts could be used including 12.5, 25, 37.5, 75 or 100 mg. The diclofenac preferably has a loss on drying of not less than 0.5%, and an average particle size of greater than 100 microns, and less than 400 microns.
Uncoated diclofenac tablets containing 50 mg. of diclofenac potassium were prepared based on the formulations given in Table 1 below. Formulations were prepared using alcoholic granulation (Tablet C) and direct compression (Tablet B).
Stability tests were conducted in various blister packaging materials on the tablet cores (Tablet B and Tablet C), and on Tablet B tablets coated with an aqueous polymer coating suspension (Tablet BA) and an alcoholic polymer coating solution (Tablet BB). Stability testing was restricted to three different blister types. The properties of the forming and lidding films used in the three blister materials tested are as follows:
An appropriate quantity of tablet cores (Tablets B and C) and coated tablets (Tablets BA and BB), original packaging (blisters 1-3) was stored in Weiss-Enet climatic chambers for six months under the following conditions of temperature and relative humidity:
Samples were withdrawn at suitable intervals and subjected to testing for Diameter, thickness, Hardness, Weight, Disintegration time in water (37° C.), Water content, Dissolution buffered ph 7.5 medium, and Assay. The measurements were performed on six tablet cores or coated tablets taken at random in all instances, and the average values were recorded. The results are given in Tables 2-7 below.
Using the dissolution test procedure described in the European Pharmacopeia, the dissolution profiles for two tablets (Ex. 3a and 3b) having the composition set forth in Table 8 were generated. The only difference between the two tablets was the source of the diclofenac potassium. Dissolution profiles of 50 mg. diclofenac potassium tablets marketed as Voltaren Rapid and Voltfast were also generated, and graphs of the contrasting dissolution profiles were superimposed, to produce
A further comparative test was carried out on immediate release formulations T1 and T2, as reported below in Table 9. A comparative bioavailabilty study was carried out on 6 healthy volunteers of both sexes in order to evaluate the in vivo results of the pharmacokinetic profiles of the present formulations if compared to those of a bioequivalent fast release formulation such as Voltaren Rapid® (50 mg of diclofenac potassium), by Novartis. The results, which are reported in
Throughout this application, various publications are referenced. The disclosures of these publications in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art to which this invention pertains. It will be apparent to those skilled in the art that various modifications and variations can be made in the present invention without departing from the scope or spirit of the invention. Other embodiments of the invention will be apparent to those skilled in the art from consideration of the specification and practice of the invention disclosed herein. It is intended that the specification and examples be considered as exemplary only, with a true scope and spirit of the invention being indicated by the following claims.
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