text:
Hotel for sale in Dartmoor National Park, TQ13
www.rightmove.co.uk/property/71701973
A Fabulous 17th Century, Grade II Listed 20+ Bed Hotel
Well Established Business Presented to an Extremely High Standard Throughout
Operated Under Management Offering Genuine Potential for Owner Driven Growth
Self Contained Mews with 8 rooms available by Separate Negotiation
Moretonhampstead is an ancient market town situated within Dartmoor National Park in the centre of Devon. The town is surrounded by some of the finest countryside in England ? rolling hills covered in mature woodland, open tors, spectacular views and ample opportunities to explore. The town is essentially a village in character and is located at almost the exact geographical centre of the County, making it an ideal base to explore not only the unique features of Dartmoor but also the beautiful South and North Devon coasts. The Cathedral City of Exeter is approximately 14 miles away and the White Hart is approximately 12 miles to the market town of Newton Abbot, 14 miles from Okehampton and around 40 miles to the City of Plymouth. Plymouth, Newton Abbot and Exeter all have main line railway links; Exeter has an international airport.
The building which is reputed to date from 1639, is Grade II Listed and has been a focal point of village life in Moretonhampstead for centuries. The White Hart Hotel, which has been awarded AA 3 Star, a TripAdvisor Certificate of Excellence alongside the Taste of the West Gold Award 2017 is a well-established business and offers all the modern comforts of a luxury hotel within a traditional setting. The premises have over the years been refurbished to a particularly high standard with quality fixtures and fittings. The Hotel has 17 beautifully appointed en suite bedrooms with a further 3 en suite rooms being used for staff accommodation and storage. The premises were purchased by our client in 2012, during this time the owner has invested heavily in the infrastructure and fabric of the building including the fitting of a state of the art heating & hot water system, refurbishment of the majority of bedrooms to a superior standard and the upgrading of majority of the commercial catering equipment. The Hotel, which is dog friendly, has built a strong reputation for providing excellent accommodation and cuisine with a welcoming atmosphere. The restaurant and bar, which is open to non-residents, offers fresh, seasonal, local produce prepared to the highest standard and is complimented by a range of local real ales and a hand-picked wine list.
With partly glazed double doors to
Fully carpeted with attractive Oak Reception desk, recessed down lighters, seating area with easy chairs, sofas and tables. Archway to
Open fireplace with marble surround and mantel over, seating for 14 at upholstered chairs and settees with hardwood tables. Recessed down lighters.
The White Hart Hotel is a well-established former Posting House offering a superior dining experience with luxury accommodation, whilst retaining the character and ambience of a traditional country hostelry. The hotel is family owned, however the day to day business is operated by a Manager with the support of an experienced team of staff including an Assistant Manager, a MOD day and night, Housekeeper, Head Chef and Sous Chef with further waiting staff. The business draws trade year round with guests travelling from all over the world to visit the iconic Dartmoor National Park. The White Hart is well supported locally too and is at the centre of the local community.
The sale of the White Hart Hotel provides a unique opportunity to buy a fabulous Dartmoor property and business, presented to an extremely high standard throughout. It would ideally suit an owner/operator 'couple' who could capitalise on running the business themselves and thus maximising the bottom line profits. Profit & Loss trading figures will be provided to bona fide applicants following a formal viewing arranged through the Sole Selling Agents, Bettesworths.
All mains services are connected to the property. The property is centrally heated throughout.
THE MORETON SUITE
A boardroom style function room with large central table seating 12 and door to
The hotel has a fully integrated IT system including on line hotel and restaurant bookings.
There are 17 Bedrooms all with en suite facilities arranged over the first and second floors. All the bedrooms are presented to a very high standard, each having flat screen televisions, CD players, tea & coffee making facilities and complimentary toiletries. The bedrooms are arranged as follows: 2 Superior rooms, 1 Superior twin, 1 Superior Family Room, 5 Twin/King, 4 Doubles, 2 'Cosy' Doubles and 2 'Cosy' Singles. There are 3 more double rooms currently used for staff and storage. Tariff - Off Season Rates on a B&B basis £55- £130 High Season Rates on a B&B basis £65 - £150.
MANAGER'S/OWNER'S FLAT
Arranged as open plan Kitchen/Diner/lounge with Juliette balcony, 2 double bedrooms and bathroom.
Between the Main Hotel and the Stag Suite there is an attractive paved COURTYARD AREA with seating for around 20 at hardwood tables and chairs. The Courtyard has an adjustable awning and attractive lighting for evening use.
THE MEWS (Available by separate negotiation)
The 8 deluxe rooms opposite the hotel benefit from an open plan communal lounge area. Four rooms on the ground floor and four on the top floor. One with inter-connecting door between bedrooms. Self-contained with separate services. Mews 1 ? Small double Mews 2 ? Family Room with Kingsize bed plus pull out sleeper couch. Mews 3 ? Double room (can be interconnecting with bedroom 4) Mews 4 ? Superking or twin Mews 5 ? Double room with Kingsize bed Mews 6 ? Family room with King size bed plus pull out sleeper couch Mews 7 ? Double Room with King size bed Mews 8 ? Room with Superking bed or Twin Tariff - Off Season Rates on a B&B basis £55- £120 High Season Rates on a B&B basis £65 - £120
£46,100. Please note this is not rates payable. For information, we advise you to contact the Local Authority, Teignbridge District Council.
Timber topped Bar Servery with beer fonts, bottle fridge, shelving and stripped floorboards. Seating for 20 at upholstered chairs and bar stools with hardwood tables. Wood burning stove with brick surround and mantle over and attractive recessed lighting.
FRONT - 26 Covers. Fully carpeted, exposed stonework to walls, wall light points, beamed ceiling and 2 sets of double doors to REAR ? further 12 covers. Living flame gas fire with stone surround. Concealed servery area.
Very well equipped with a wide range of commercial equipment to include Blue Seal gas chargrill, Blue Seal 6 ring gas burner stove with gas oven, Rational 5 Senses electric oven, Robo Coupe Food Processor, Iberital Lanna Expresso Coffee machine and separate grinder.
Single stainless steel sink with double drainer, commercial dishwasher, deep single sink and drainer. Stainless steel preparation table, tiled walls and floor.
With 1 Foster double door upright freezer, 2 Foster double door upright fridges. Tiled floor.
Commercially equipped with 2 Vaillant Combi boilers and 2 x 500 Ltr water tanks.
Housing temperature controlled Beer Cellar, Wine & Bottle Store and general storage space.
Spacious carpeted Function Room with seating for 60, flat screen television, recessed lighting, separate Bar Servery and Ladies and Gents Cloakrooms.
To view this media, please visit the on-line version of this page at www.rightmove.co.uk/commercial-property-for-sale/property-71701973.html
Disclaimer - Property reference 8577607. The information displayed about this property comprises a property advertisement. Rightmove.co.uk makes no warranty as to the accuracy or completeness of the advertisement or any linked or associated information, and Rightmove has no control over the content. This property advertisement does not constitute property particulars. The information is provided and maintained by Bettesworths, Torquay. Please contact the selling agent or developer directly to obtain any information which may be available under the terms of The Energy Performance of Buildings (Certificates and Inspections) (England and Wales) Regulations 2007 or the Home Report if in relation to a residential property in Scotland.

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text:
The Reality of Software Testing in ...
Background Slides for ISCRAM 2010 K...
Testing Methods Carl Smith National Certificate Year 2 – Unit 4
Unit 4 objectives

Apply simple analysis and design techniques to the software development process.

Develop basic high-level code using an appropriate procedural programming language.

Use suitable testing methods to ascertain the correctness of a working piece of code.

Produce appropriate documentation for a given program application.

Errors in your code

What are the types of errors we need to test for?

Syntax Errors

Syntax Errors: errors in the use of the Pascal language.

The most common examples are missing semicolons and misspelled words.

These errors are detected by the compiler and an error message is produced.

Runtime Errors

Runtime Errors: a program stops executing because a program statement, although syntactically correct, produces a meaningless or impossible result e.g. dividing by zero

Logic Errors

Logic Errors: a program completes execution but the results expected are not correct.

A calculation may have been coded incorrectly or the sequence of instructions may be incorrect

The level of error checking provided by the compiler and the meaningfulness of error messages displayed vary depending on the implementation of the development environment (e.g. TP)

Detecting Errors

The compiler will detect syntax errors. Execution of the program will terminate when a run-time error is present

It is important that we have a strategy for detecting the existence of logic errors

Black Box Testing

Also known as functional testing . A software testing technique whereby the internal workings of the item being tested are not known by the tester. For example, in a black box test on a software design the tester only knows the inputs and what the expected outcomes should be and not how the program arrives at those outputs. The tester does not ever examine the programming code and does not need any further knowledge of the program other than its specifications.

Advantages & Disadvantages

The advantages of this type of testing include:

The test is unbiased because the designer and the tester are independent of each other.

The tester does not need knowledge of any specific programming languages.

The test is done from the point of view of the user, not the designer.

Test cases can be designed as soon as the specifications are complete.

The disadvantages of this type of testing include:

The test can be redundant if the software designer has already run a test case.

The test cases are difficult to design.

Testing every possible input stream is unrealistic because it would take a inordinate amount of time; therefore, many program paths will go untested.

White Box Testing

Also known as glass box , structural , clear box and open box testing . A software testing technique whereby explicit knowledge of the internal workings of the item being tested are used to select the test data. Unlike black box testing , white box testing uses specific knowledge of programming code to examine outputs. The test is accurate only if the tester knows what the program is supposed to do. He or she can then see if the program diverges from its intended goal. White box testing does not account for errors caused by omission, and all visible code must also be readable.

For a complete software examination, both white box and black box tests are required.

The Test Plan

A test plan may or may not form part of the technical specification , but one needs to be produced.

It should be developed by a systems analyst with an overview of the entire system being produced (and certainly not by a programmer involved in the coding process)

The Test Plan - 2

Individual programmers will test their own programs as part of the development process.

The test plan may provide for testing of individual programs, but should concentrate on testing how the various elements of the new system “co-operate” together. It must test the entire system.

Successful Testing

Since the purpose of testing is to discover “bugs”, a test is termed successful if it uncovers an error, and is unsuccessful if the program behaves as it should.

Try to “break” your program – don’t try to convince yourself it works.

Involve others in your testing…!

Testing Stages

Design your test strategy

Record your test plan

List the results

Example Test Plan

Table here…

Summary

We covered:-

National Certificate Unit 4 objectives

The importance of testing

Syntax, Runtime and Logic errors

Successful Testing

Example Test Plan

Any Questions?

Structuring Problem-based Learning - Mine, Ours and Yours

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County Government Jobs, Employment in DeKalb County, GA
County Government jobs in DeKalb County, GA
DHR - DFACS (10)
OMT Consultants, LLC (2)
SAT/ACT Instructors for Fulton County Schools
SAT/ACT Instructors for Fulton County Schools. This is a part time, flexible role teaching after school in Fulton County Schools....
Atlanta [GA]
Completion or Government RFI’s, RFQV’s, and RFP’s Coordinate and execute contracts for government opportunities....
Budget Management Analyst Principal
Reviews proposed legislation to determine financial impact on the County. Three years of experience in local government budget and management analysis or...
View all DeKalb County, GA jobs in DeKalb County, GA - DeKalb County, GA jobsSalary Search: Budget Management Analyst Principal salaries in DeKalb County, GALearn more about working at Dekalb County, GaRelated forums: DeKalb County, GA
DHS/DFCS -Economic Support Specialist 2- ABD - Clayton Count...
$26,672 - $32,171 a year
DHS/DFCS -Economic Support Specialist 2- ABD - Clayton County. The department is one of the largest agencies in state government with an annual budget of $1.8...
View all DHR - DFACS jobs in Jonesboro, GA - Jonesboro jobsSalary Search: Dhs Dfcs salaries in Jonesboro, GARelated forums: DHR - DFACS - Jonesboro, Georgia
The department is one of the largest agencies in state government with an annual budget of $1.8 billion and approximately 8500 employees....
$29,246 a year
GA in Fulton County. State government with an annual budget of $1.8 billion and approximately 8500. Department of Human Services....
Additionally, DCS will have oversight of private, county and municipal probation operations. Experience working with Service Providers in the Metro Atlanta area...
(Listed on DeKalb County Government Worksite). DeKalb County Fleet Maintenance department is seeking several qualified Technicians....
Current state government. This position will serve Gwinnett County, Region 13. Department is one of the largest agencies in state government with an annual...
WE DeKalb Program (DeKalb County homeownership down payment grant program):. Present WE DeKalb to local business and municipal governments from a recruitment...
View all Decide DeKalb Development Authority jobs in Decatur, GA - Decatur jobsSalary Search: Senior Marketing Manager salaries in Decatur, GALearn more about working at Decide Dekalb Development AuthorityRelated forums: Decide DeKalb Development Authority - Marketing Manager - Decatur, Georgia
Security Officer-Armed POST Certification Required
View all AlliedBarton Security Services jobs in Union City, GA - Union City jobsSalary Search: Security Officer Armed Post Certification salaries in Union City, GALearn more about working at Alliedbarton Security ServicesRelated forums: AlliedBarton Security Services - Union City, Georgia
Office in Cobb County. In assigned counties, securing court dates for judges, submitting process. State government with an annual budget of $1.8 billion and...
Get email updates for the latest County Government jobs in DeKalb County, GA

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text:
FOP FILES SUIT ON LIMITED-DUTY POLICY - The Washington Post
FOP FILES SUIT ON LIMITED-DUTY POLICY
By Stephen Buckley July 13, 1990
The union representing D.C. police officers filed suit yesterday in an attempt to block a police department policy on limited duty that the union says unfairly affects pregnant, ill and injured officers.
A Superior Court hearing to determine if the Fraternal Order of Police will be granted its request for a temporary restraining order is scheduled for today.
Under the previous limited-duty rules, pregnant officers and those who had suffered illnesses or injuries while off duty were assigned to desk jobs or administrative work. Only officers expected to recover from their medical conditions were eligible.
The department's new policy, adopted July 8, decrees that officers who had been eligible for limited duty must go on sick leave, annual leave or leave without pay.
In its lawsuit, the FOP said that the department has violated the District's Human Rights Act and the 14th Amendment, which guarantees equal protection under the law.
Gary Hankins, chairman of the FOP labor committee, said yesterday that the new policy affected at least 75 officers who were on limited duty when the change took place. He said it would affect an unknown number of officers who are pregnant or have become ill or injured since the policy change.
Hankins said he hoped a restraining order would "prevent the women who are now pregnant and hiding it, or considering abortion, from having to do either. And we want to secure a permanent limited-duty program that doesn't penalize officers, men or women, who are injured off duty."
Lt. Reginald Smith, spokesman for the police department, was not available for comment yesterday.
Hankins designated two pregnant officers last week whom colleagues could contact with questions and concerns. Those women -- Cora Lee Clark of the 3rd District and Alexandra Albright of the 2nd District -- said yesterday that about 40 officers had contacted them to express anxiety over the policy change.
"People are frustrated," said Clark, a 16-year member of the force. "They're afraid that their kids will suffer. They're concerned about what they'll do when they stop getting paid and don't have any health insurance."
Clark and Albright said that several officers have told them they are going to hide their pregnancies or injure themselves on purpose while on duty in order to be placed on limited duty.
Albright said she told the women who are hiding pregnancies "that they ought to just go ahead and go to the {D.C. police and fire department} clinic. That way, they're not breaking general order policy. And I tell them the lawyers sound pretty optimistic that we'll be able to get limited duty back."
One 32-year-old officer, who has been on the force seven years and who is four months pregnant, said she has disguised her pregnancy by wearing larger clothes. When colleagues ask if she's pregnant, the officer said, "I tell them I don't want to talk about it."
The officer, who asked not to be identified, said she is unmarried and has 9- and 10-year-old sons, and would injure herself on duty "for my family to be taken care of and fed . . . . I'll do it if that's the only way that the department will let me be paid and still work."

value: This website is an American daily newspaper published in Washington, D.C. It is the most-widely circulated newspaper within the Washington metropolitan area, and has a large national audience. Daily broadsheet editions are printed for D.C., Maryland, and Virginia.


text:
A Picture of Guilt - Audiobook | Audible.com
©2003 Poisoned Pen Press (P)2016 Libby Fischer Hellmann
This story had me in the first chapter! I had no idea that it would reference my home town of White Sulphur Springs WV and the Greenbrier hotel! And the reference to the New River George River. It was really fun listening to this. The entire story was fun with a great mystery, action and a little love. It was so easy to listen to. But I do think she better get some control over her 13 year old daughter!
An engrossing addition to the Ellie Foreman series
She does her civic duty, takes the videotape to the defense attorney (figuring at this point, with the trial about to start, the police won't be interested in new evidence for the defense), and testifies at trial. Unfortunately, the tape has some RF damage that she can't account for, and the prosecutor pretty much takes her apart. They guy is convicted anyway.
Even more unfortunately for Ellie, that's just the beginning. The prosecutor made her look unprofessional, she's now attached to a bit of controversy, and it turns out someone else is much more unhappy about her finding that tape than the prosecutor was. No one wants to hire her right now. Everyone assures her it will pass, but right now she can't get the work she depends on.
When she starts to suspect she's being followed, things start to get scary.
When the murdered woman's best friend tracks her down, claims that she (the friend) is being followed because she knows more than she told at the trial, and is shortly thereafter killed in a car crash, Ellie becomes convinced she needs to solve the crime(s) herself, while those around her, who care about her safety, think it's proof she should have kept her mouth shut, and maybe ought to take a vacation out of town for a while.
But that's not the Ellie we have, or will, come to love. She knows something is wrong, and she needs to set it right. She keeps digging. David is frustrated enough that she's taking risks when all he wants to do is keep her safe. He loves her, he values security, and he wants to keep Ellie safe--how can Ellie possibly find this confining? But it gets worse when her digging connects to a client of his...
It's a satisfyingly complex mystery, and Ellie, David, and even Rachel, at that awkward age of being aa new teen, are all going through some important emotional growth and challenges here.
I received a free copy of this audiobook from the author, and am reviewing it entirely by my own choice.
I really enjoyed this story. It was well written, descriptive and full of twists and turns.
It kept me interested and turning the pages all the way through to the very end! It's full of twists and turns and tons of suspense. Looking forward to the next book!
A quick and entertaining listening to this audiobook. I knew the direction the story was heading far earlier than I should have, may be because I read so many books in this genre and not because of any particular tells in the story.

value: This website is an American online audiobook and podcast service that allows users to purchase and stream audiobooks and other forms of spoken word content. This content can be purchased individually or under a subscription model where the user receives "credits" that can be redeemed for content monthly and receive access to a curated on-demand library of content.


text:
Animal Protection and Rescue League - Wikipedia
(Redirected from APRL)
and Rescue League
Kath Rogers and Bryan Pease
San Diego and Orange Counties,
" Protecting Animals
Promoting Compassion "
The Animal Protection and Rescue League (APRL) is an American grassroots animal rights organization based in California's San Diego and Orange Counties.
In 2003 APRL was formed in San Diego by animal rights activist Bryan Pease and Kath Rogers as a 501(c)(3) nonprofit national organization. [1] Subsequently the Orange County chapter of APRL was formed in Irvine California and is staffed entirely by volunteers that follow the same mission of animal rights as the national organization. [2]
1 Activities and campaigns
1.1 Thrift Store
1.2 Cruelty-free Eating
1.3 SoCal VegFest
1.4 Ban Foie Gras
1.5 Prevention of Farm Animal Cruelty
1.6 The GO VEGAN Billboard Campaign
1.7 Orange County Beach Cleanup
1.8 Protesting Animals Used in Entertainment
1.9 Aide Companion Animals
1.10 Helping the Catalina Harbor Cats
1.11 Opposition to Kapparot
1.12 Grant Program
2 Legal advocacy
2.1 Animal Protection and Rescue League et al. v. The State of California et al.
Thrift Store[edit]
The APRL thrift store was founded in February of 2006. [3] All proceeds from the store went to campaigns and programs to help animals through the Animal Protection and Rescue League. The friendly staff members at the store were all committed to the store and to APRL's mission to protect animals. The store operated because of the hard work of this dedicated thrift store team. On July 9th 2017 the APRL Thrift Store closed after a great 10 year run as a nonprofit small business.[4]
Cruelty-free Eating[edit]
Through APRL's GO VEGAN, College Outreach, and Vegan Outreach campaigns, volunteers distribute pamphlets to spread the word about the benefits of a plant-based diet to patrons at popular gathering spots like Downtown Disney, Knott's Berry Farm, The Outlets at Orange, the Irvine Spectrum, swap meets and college campuses. We estimate that for every 200 pamphlets distributed, one person goes vegan. That's 100 animals saved per year, or thousands over the course of a new vegan's life. APRL has given out hundreds of thousands of pamphlets and through this alone, we’ve saved millions of lives
SoCal VegFest[edit]
The SoCal VegFest is run by dedicated volunteers as a project of Animal Protection and Rescue League. SoCal VegFest is a yearly event, normally in mid-fall, designed to engage curiosity and inspire consciousness in people of all ages. The event include free plant-based food samplings, musical entertainment, guest speakers, cooking demonstrations, raffles, interactive booths, food vendors, humane organizations, an enjoyable children’s area with a variety of engaging opportunities especially for kids, and more. The purpose of SoCal VegFest is to introduce Southern Californians and others to the benefits of healthy conscious living. Our goal is to inspire and support anyone who wants to learn more about living a more healthy, environmentally friendly, and compassionate life.
Ban Foie Gras[edit]
APRL's Stop Foie Gras campaign has released groundbreaking video footage of extreme cruelty from all three foie gras farms in the U.S. and several in France.[5] APRL was instrumental in passing legislation in California and Chicago against this cruelty. See www.banfoiegras.org for more info on this campaign.
Prevention of Farm Animal Cruelty[edit]
APRL is a member of Californians for Humane Farms, a coalition of animal protection groups working to pass the Prevention of Farm Animal Cruelty Act—an initiative that will appear on California's November 2008 ballot. APRL led the signature gathering phase of the Yes on Prop 2 (Farm Animal Cruelty Prevention Act) campaign in Southern California. In 2017 APRL is again taking part in the signature gathering phase of the updated Prevention of Farm Animal Cruelty Act.[6]
The GO VEGAN Billboard Campaign[edit]
APRL erected two billboards on December 30, 2014, next to the I-5 freeway in Los Angeles. Together, APRL estimates, they are getting 300,000 impressions per day, or 2 million impressions per week. It would be great to keep them up longer and move them around to increase their exposure. The Orange County chapter of Animal Protection & Rescue League (with assistance from PETA, which provided a generous grant) spent most of its annual budget already on the billboards and lacks the funds to keep them up.
Orange County Beach Cleanup[edit]
To protect marine animals from ingesting plastics and debris, which causes grave harm, APRL organizes monthly beach cleanups. They supply buckets, trash bags, gloves, reach extending sticks, and sanitizing wipes for volunteers to cleanup the Southern California beaches. Volunteers are asked to help clean up the beaches in the morning. Then at noon have a vegan lunch.
Protesting Animals Used in Entertainment[edit]
APRL protests rodeos, bull riding, animal circuses, sea world, and elephant rides. They work with local government to end the use of exotic animals and end all cruel practices at fairs and Zoos.[7]
Aide Companion Animals[edit]
APRL save strays, educates about Spaying and Neutering pets, and promote pet adoption to reduce killing in the wild and in shelters. APRL has gotten many OC cities to ban the retail sale of dogs and cats and many pet stores to closes after advocacy and protest campaigns.[8] [9]
Helping the Catalina Harbor Cats[edit]
There is a colony of more than 30 feral cats living in the rugged landscape of Catalina ("Cat") Harbor on Catalina Island. Some of the cats have sustained permanent injuries from dog attacks and sadistic people. APRL started a fundraising campaign to provide needed services such as food, shelter, and medical aid.
Opposition to Kapparot[edit]
APRL protested killing of Kapparot chickens and sought legal actions.[10] [11]
Some of the other organizations APRL has supported:
Synergy Animal Rescue
Animal Protection and Rescue League et al. v. The State of California et al.[edit]
Injunction was filed March 10, 2008.
An injunction was granted to place a guideline rope on the La Jolla Children’s pool beach to protect seals and their pups until May 30, 2008.
Timeline of rights
^ "Why Don't Vegans Care About People?". 15 August 2012. Retrieved 4 December 2017.
^ "Animal Protection & Rescue League". Animal Protection & Rescue League. Retrieved 4 December 2017.
^ "New Thrift Shop on Newport Avenue Is All About the Animals". obrag.org. Retrieved 3 December 2017.
^ "Animal Protection & Rescue League Thrift Store - CLOSED - Clairemont - San Diego, CA". Yelp. Retrieved 3 December 2017.
^ "Ducks and Geese Exploitation - Foie Gras - 37 - Animal Exploitation Photo Journal and Gallery from All-Creatures.org". www.all-creatures.org. Retrieved 3 December 2017.
^ "California ballot initiative seeks to prevent animal cruelty, protect food safety in the Golden State : The Humane Society of the United States". www.humanesociety.org. Retrieved 4 December 2017.
^ "Tai the Elephant Abused Prior to Filming of Robert Pattinson Vehicle 'Water For Elephants,' Animal Rights Group Says". 9 May 2011. Retrieved 4 December 2017.
^ "Original Russo's Pet Experience Now Targeted by Puppy Mill Foes". 7 December 2011. Retrieved 4 December 2017.
^ "San Diego To Consider Ban On Retail Sale Of Animals". Retrieved 4 December 2017.
^ "Jewish holiday ritual involving chicken slaughter survives a court test". 19 September 2015. Retrieved 3 December 2017.
^ "Attorneys try to save chickens from being slaughtered in Jewish ritual in Irvine". 5 October 2016. Retrieved 3 December 2017.
"California Law Bans Production, Sale of Foie Gras". www.upc-online.org. Retrieved 3 December 2017.
"Mmmm... cruely". 7 December 2005. Retrieved 3 December 2017.
"La Jolla Children's Pool Rope Meant To Protect Seals Removed Today". Retrieved 3 December 2017.
"What is foie gras? - StopForceFeeding.com". www.stopforcefeeding.com. Retrieved 4 December 2017.
"7 Awesome Cities That Have Taken a Stand Against Puppy Mills - One Green Planet". www.onegreenplanet.org. Retrieved 4 December 2017.
"Group seeks indictment of former OC Animal Control officers who 'barbarically' slit deer's throat". 17 April 2015. Retrieved 4 December 2017.
"Woman who seeks memorial says she values humans and fish". 1 November 2012. Retrieved 4 December 2017.
Retrieved from "https://en.wikipedia.org/w/index.php?title=Animal_Protection_and_Rescue_League&oldid=813727431"
This page was last edited on 4 December 2017, at 22:52.

value: This website is the English-language edition of the free online encyclopedia Wikipedia. It was founded on 15 January 2001 as Wikipedia's first edition and, as of October 2021, has the most articles of any edition, at 6,412,521.


text:
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Good Thyme in the Garden Tickets, Wed, Aug 15, 2018 at 8:00 PM | Eventbrite
Wed, August 15, 2018, 8:00 PM – 11:00 PM IST
Good Thyme Thursdays presents an evening of music and poetry in celebration of Fleadh Cheoil na hEireann's arrival in Drogheda, Co. Louth. In a special edition of the renowned series usually run at Good Thyme Cafe on the last Thursday of every month, the event is moving both venue and date for this unique event. The concert will take place in the beautiful, intimate surroundings of the newly opened Garden of Remembrance on the grounds of the Augustinian Church, Drogheda. Featuring on the night will be Joy Dunlop (Scots Gaelic singer, UK), Stephen James Smith (poet & spoken word artist, Ireland), Robbie Boyd (singer-songwriter, UK), Short Shorts (dynamic music duo, Ireland) and Glé-gheal Gáire (traditional Irish group, Ireland).
Robbie Boyd is a singer, songwriter and musician from London, United Kingdom. He has performed live on ITV’s ‘This Morning’ twice, been regularly aired on BBC Radio 2 by the likes of Graham Norton, Paul O’Grady and Jeremy Vine, and is currently on a World Tour to promote his new album, ‘Break The Chain’, adding Australia to the extensive list of countries he’s toured, from America, Argentina, Europe, Scandinavia to Japan. He’s supported The Kooks, Mark Ronson, Jack Garratt, McFly, Jack Savoretti and Daughter, and he’s even had Suggs open up for him! Robbie’s co-written with the legendary Ray Davies from the Kinks, and written and recorded with some of Nashville’s finest.
Robbie’s honest and inspiring songs have captivated a worldwide audience and his success is a confirmation of the many hours he’s spent busking on the streets of London, Europe and America, where he honed his craft, along with the hundreds of shows he’s played around the world, and the purpose with which he works.
Short Shorts are an up-and-coming Irish band passionate in creating unique catchy originals, performing fun & memorable covers, bringing a smile to your face, and flaunting breezy short shorts! From the midlands, the two piece band of Adrian Rabbitte and Adam Cunningham formed one year ago with the band name being created on the way to a premier gig. They have recorded originals to release on their highly popular Youtube channel as well as performed in venues across the country.
'Who knows what will await the short shorts lovers on their journey!! Probably something, most likely, we dunno, but hey, hang around for the ride, we're hoping to go to some interesting places...'
Glé-gheal Gáire
Glé-gheal Gáire are a recent and valuable addition to the traditional music scene. The members hail from various parts of County Louth - Drogheda to Dromiskin. They offer a lively mix of instruments and voices, tunes and songs not to mention the odd piece of poetry. A resounding 'hit' from previous Good Thyme Thursdays sessions, Glé-gheal Gáire are, as their name suggests, light, bright, and sure to entertain!
Good Thyme in the Garden at St. Augustine's Church

value: This website is an American event management and ticketing website. The service allows users to browse, create, and promote local events.


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Patent US7476652 - Acidic insulin preparations having improved stability - Google PatentsSearch Images Maps Play YouTube News Gmail Drive More »Sign inPatentsThe invention relates to a pharmaceutical formulation comprising a polypeptide selected from the group consisting of insulin, an insulin metabolite, an insulin analog, an insulin derivative and combinations thereof; a surfactant or combinations of two or more surfactants; optionally a preservative or...http://www.google.com/patents/US7476652?utm_source=gb-gplus-sharePatent US7476652 - Acidic insulin preparations having improved stabilityAdvanced Patent SearchTry the new Google Patents, with machine-classified Google Scholar results, and Japanese and South Korean patents.Publication numberUS7476652 B2Publication typeGrantApplication numberUS 11/089,777Publication dateJan 13, 2009Filing dateMar 25, 2005Priority dateJun 18, 2002Fee statusPaidAlso published asCA2490116A1, CA2490116C, CN1662252A, CN102133393A, CN102133393B, DE10227232A1, EP1517697A1, EP1517697B1, EP2305288A2, EP2305288A3, US7713930, US20040048783, US20050171009, US20090082255, US20100216692, WO2003105888A1Publication number089777, 11089777, US 7476652 B2, US 7476652B2, US-B2-7476652, US7476652 B2, US7476652B2InventorsAnette Brunner-Schwarz, Norbert LillOriginal AssigneeSanofi-Aventis Deutschland GmbhExport CitationBiBTeX, EndNote, RefManPatent Citations (107), Non-Patent Citations (41), Referenced by (20), Classifications (26), Legal Events (5) External Links: USPTO, USPTO Assignment, EspacenetAcidic insulin preparations having improved stability
US 7476652 B2Abstract
The invention relates to a pharmaceutical formulation comprising a polypeptide selected from the group consisting of insulin, an insulin metabolite, an insulin analog, an insulin derivative and combinations thereof; a surfactant or combinations of two or more surfactants; optionally a preservative or combinations of two or more preservatives; and optionally an isotonicizing agent, buffers or further excipients or combinations thereof, the pharmaceutical formulation having a pH in the acidic range.
at least one preservative; and
wherein the pharmaceutical formulation has a pH in the acidic range from 1 to 6.8.
7. A pharmaceutical formulation comprising Gly(A21), Arg(B31), Arg(B32)-human insulin,
17. The pharmaceutical formulation as claimed in claim 1, wherein the at least one chemical entity is present in a concentration of 5-200 μg/ml.
18. The pharmaceutical formulation as claimed in claim 17, wherein the at least one chemical entity is present in a concentration of 5-120 μg/ml.
19. The pharmaceutical formulation as claimed in claim 18, wherein the at least one chemical entity is present in a concentration of 20-75 μg/ml.
24. A pharmaceutical formulation comprising Gly(A21), Arg(B31), Arg(B32)-human insulin:
at least one preservative chosen from cresol; and
wherein the pharmaceutical formulation has a pH in the acidic range from 3.5 to 4.5.
25. The pharmaceutical formulation as claimed in claim 1, further comprising one or more excipients chosen from acids, alkalis and salts. Description
This application is entitled to the benefit of U.S. Provisional Application 60/409,338, filed Sep. 9, 2002, and Federal Republic of Germany Application 10227232.8-41, filed Jun. 18, 2002.
The invention relates to a pharmaceutical formulation comprising a polypeptide selected from the group consisting of insulin, an insulin metabolite, an insulin analog, an insulin derivative or combinations thereof; a surfactant or combinations of two or more surfactants; optionally a preservative or combinations of two or more preservatives; and optionally an isotonicizing agent, buffers or further excipients or combinations thereof, the pharmaceutical formulation having a pH in the acidic range. These formulations can be employed for the treatment of diabetes, and are particularly suitable for preparations in which a high stability to thermal and/or physicomechanical stress is necessary. The invention likewise relates to parenteral preparations which contain such formulations and can be used in diabetes and to methods for producing the preparations and for improving the stability of insulin preparations.
BACKGROAND OF THE INVENTION
In the healthy person, the release of insulin by the pancreas is strictly coupled to the concentration of blood glucose. Elevated blood glucose levels, such as occur after meals, are rapidly compensated by a corresponding increase in insulin secretion. In the fasting state, the plasma insulin level falls to a basal value which is adequate to guarantee a continuous supply of insulin-sensitive organs and tissue with glucose and to keep hepatic glucose production low at night. The replacement of endogenous insulin secretion by exogenous, mostly subcutaneous administration of insulin, as a rule does not approximate the quality of the physiological regulation of the blood glucose described above. Often, deviations of blood glucose upward or downward occur, which in their severest forms can be life-threatening. In addition, however, blood glucose levels which are increased for years without initial symptoms are a considerable health risk. The large-scale DCCT study in the USA (The Diabetes Control and Complications Trial Research Group (1993) N. Engl. J. Med. 329, 977-986) demonstrated clearly that chronically elevated blood glucose levels are essentially responsible for the development of diabetic late damage. Diabetic late damage is microvascular and macrovascular damage which is manifested, ander certain circumstances, as retinopathy, nephropathy or neuropathy and leads to loss of sight, kidney failure and the loss of extremities and is moreover accompanied by an increased risk of cardiovascular diseases. In view of this, an improved therapy of diabetes should be aimed at keeping the blood glucose as closely as possible in the physiological range. According to the concept of intensified insulin therapy, this should be achieved by repeated daily injections of rapid- and slow-acting insulin preparations. Rapid-acting formulations are given at meals in order to level out the postprandial increase in the blood glucose. Slow-acting basal insulins should ensure the basic supply with insulin, in particular during the night, without leading to hypoglycemia.
Insulin is a polypeptide of 51 amino acids, which are divided into 2 amino acid chains: the A chain having 21 amino acids and the B chain having 30 amino acids. The chains are connected to one another by means of 2 disulfide bridges. Insulin preparations have been employed for diabetes therapy for many years. Not only are naturally occurring insulins used, but recently also insulin derivatives and analogs.
Insulin analogs are analogs of naturally occurring insulins, namely human insulin or animal insulins, which differ by substitution of at least one naturally occurring amino acid residue with other amino acids and/or addition/removal of at least one amino acid residue from the corresponding, otherwise identical, naturally occurring insulin. The amino acids can in this case also be those which do not occur naturally.
Insulin derivatives are derivatives of naturally occurring insulin or an insulin analog which are obtained by chemical modification. This chemical modification can consist, for example, of the addition of one or more specific chemical groups to one or more amino acids. As a rule, insulin derivatives and insulin analogs have a somewhat modified action compared with human insulin.
Insulin analogs having an accelerated onset of action are described in EP 0 214 826, EP 0 375 437 and EP 0 678 522. EP 0 124 826 relates, inter alia, to substitutions of B27 and B28. EP 0 678 522 describes insulin analogs which in position B29 have various amino acids, preferably proline, but not glutamic acid. EP 0 375 437 includes insulin analogs with lysine or arginine in B28, which can optionally be additionally modified in B3 and/or A21.
In WO 92/00321, insulin analogs are described in which at least one amino acid of the positions B1-B6 is replaced by lysine or arginine. According to WO 92/00321, insulins of this type have a prolonged action. The insulin analogs described in EP-A 0 368 187 also have a delayed action.
The insulin preparations of naturally occurring insulins on the market for insulin substitution differ in the origin of the insulin (e.g. bovine, porcine, human insulin), and also the composition, whereby the profile of action (onset of action and duration of action) can be influenced. By combination of various insulin preparations, very different profiles of action can be obtained and blood sugar values which are as physiological as possible can be established. Recombinant DNA technology today makes possible the preparation of such modified insulins. These include insulin glargine (Gly(A21)-Arg(B31)-Arg(B32)-human insulin) with a prolonged duration of action. Insulin glargine is injected as an acidic, clear solution and precipitates on account of its solution properties in the physiological pH range of the subcutaneous tissue as a stable hexamer associate. Insulin glargine is injected once daily and is distinguished compared with other long-acting insulins by its flat serum profile and the reduction of the danger of nightly hypoglycemia associated therewith (Schubert-Zsilavecz et al., 2: 125-130(2001)).
The specific preparation of insulin glargine, which leads to the prolonged duration of action, is characterized, in contrast to previously described preparations, by a clear solution having an acidic pH. Especially at acidic pH, insulins, however, show a decreased stability and an increased proneness to aggregation on thermal and physicomechanical stress, which can make itself felt in the form of turbidity and precipitation (particle formation) (Brange et al., J. Ph. Sci 86:517-525(1997)).
The proneness to aggregation can additionally be promoted by hydrophobic surfaces which are in contact with the solution (Sluzky et al., Proc. Natl. Acad. Sci. 88:9377-9381 (1991). Surfaces which can be considered as hydrophobic are the glass vessels of the preparations, the stopper material of the sealing caps or the boundary surface of the solution with the air supernatant. In addition, very fine silicone oil droplets can function as additional hydrophobic aggregation nuclei in the taking of the daily insulin dose by means of customary, siliconized insulin syringes and accelerate the process.
Published International patent application WO 02/076495 describes zinc-free and low-zinc insulin preparations having improved stability at room and body temperature and to mechanical stress by the addition of surfactants, but does not describe the stabilization of acidic insulin preparations against hydrophobic aggregation nuclei.
It has now surprisingly been found that the addition of surfactants can greatly increase the stability of acidic insulin preparations and thus preparations can be produced which guarantee superior stability to hydrophobic aggregation nuclei for several months ander temperature stress.
The pharmaceutical preparations of the present invention contain 60-6000 nmol/ml, preferably 240-3000 nmol/ml, of an insulin, an insulin metabolite, an insulin analog or an insulin derivative.
The surfactants which can be used are, inter alia, nonionic surfactants. In particular, pharmaceutically customary surfactants are preferred, such as, for example: partial and fatty acid esters and ethers of polyhydric alcohols such as of glycerol, sorbitol and the like (Span�, Tween�, in particular Tween� 20 and Tween� 80, Myrj�, Brij�), Cremophor� or poloxamers. The surfactants are present in the pharmaceutical composition in a concentration of 5-200 μg/ml, preferably of 5-120 μg/ml and particularly preferably of 20-75 μg/ml.
The preparation can additionally optionally contain preservatives (e.g. phenol, cresol, parabens), isotonicizing agents (e.g. mannitol, sorbitol, lactose, dextrose, trehalose, sodium chloride, glycerol), buffer substances, salts, acids and alkalis and also further excipients. These substances can in each case be present individually or alternatively as mixtures.
Glycerol, dextrose, lactose, sorbitol and mannitol are customarily present in the pharmaceutical preparation in a concentration of 100-250 mM, NaCl in a concentration of up to 150 mM. Buffer substances, such as, for example, phosphate, acetate, citrate, arginine, glycylglycine or TRIS (i.e. 2-amino-2-hydroxymethyl-1,3-propanediol) buffer and corresponding salts, are present in a concentration of 5-250 mM, preferably 10-100 mM. Further excipients can be, inter alia, salts or arginine.
The invention therefore relates to a pharmaceutical formulation comprising a polypeptide selected from the group consisting of insulin, an insulin analog, an insulin derivative, an active insulin metabolite and combinations thereof; a surfactant or combinations of two or more surfactants; optionally a preservative or combinations of two or more preservatives; and optionally an isotonicizing agent, buffer substances and/or further excipients or combinations thereof, the pharmaceutical formulation being a clear solution which has a pH in the acidic range (pH 1-6.8), preferably pH 3.5-6.8, very particularly preferably 3.5-4.5.
Preferred pharmaceutical formulations of the present invention are those wherein the surfactant is selected from the group consisting of partial and fatty acid esters and ethers of polyhydric alcohols such as of glycerol and sorbitol, and polyols; the partial and fatty acid esters and ethers of glycerol and sorbitol being selected from the group consisting of Span�, Tween�, Myrj�, Brij�, Cremophor�; the polyols being selected from the group consisting of polypropylene glycols, polyethylene glycols, poloxamers, Pluronics�, and Tetronics�; the preservative being selected from the group consisting of phenol, cresol, and parabens; the isotonicizing agent being selected from the group consisting of mannitol, sorbitol, sodium chloride, and glycerol; the excipients being selected from the group consisting of buffer substances, acids, and alkalis; the insulin analog being selected from the group consisting of Gly(A21)-Arg(B31)-Arg(B32)-human insulin; Lys(B3)-Glu(B29)-human insulin; LysB28ProB29 human insulin, B28 Asp-human insulin, human insulin in which proline in position B28 has been substituted by Asp, Lys, Leu, Val or Ala and where in position B29 Lys can be substituted by Pro; AlaB26-human insulin; des(B28-B30)-human insulin; des(B27)-human insulin and des(B30)-human insulin; the insulin derivative being selected from the group consisting of B29-N-myristoyl-des(B30) human insulin, B29-N-palmitoyl-des(B30) human insulin, B29-N-myristoyl human insulin, B29-N-palmitoyl human insulin, B28-N-myristoyl LysB28ProB29 human insulin, B28-N-palmitoyl-LyB28ProB29 human insulin, B30-N-myristoyl-ThrB29LysB30 human insulin, B30-N-palmitoyl-ThrB29LysB30 human insulin, B29-N-(N-palmitoyl-γ-glutamyl)-des(B30) human insulin, B29-N-(N-lithocholyl-γ-glutamyl)-des(B30) human insulin, B29-N-(ω-carboxyheptadecanoyl)-des(B30) human insulin and B29-N-(ω-carboxyheptadecanoyl) human insulin.
A further subject of the invention is a pharmaceutical formulation such as described above, in which the insulin, the insulin analog, the active insulin metabolite and/or the insulin derivative is present in a concentration of 60-6000 nmol/ml, preferably in a concentration of 240-3000 nmol/ml (this corresponds approximately to a concentration of 1.4-35 mg/ml or 40-500 units/ml);
in which the surfactant is present in a concentration of 5-200 μg/ml, preferably of 5-120 μg/ml and particularly preferably of 20-75 μg/ml.
A further subject of the invention is a pharmaceutical formulation such as mentioned above, in which glycerol and/or mannitol is present in a concentration of 100-250 mM, and/or NaCl is preferably present in a concentration of up to 150 mM.
A further subject of the invention is a pharmaceutical formulation such as mentioned above, in which a buffer substance is present in a concentration of 5-250 mM.
The following examples illustrate, but by no means limit, the present invention.
Comparison investigations: Different preparations containing the insulin analog insulin glargine (Gly(A21),Arg(B31),Arg(B32)-human insulin) are prepared. To this end, insulin glargine is suspended in one part of water for injection, dissolved at pH 3-4, the other constituents are added, the pH is adjusted to 4.0+/−0.2 using hydrochloric acid/NaOH and the mixture is made up to the final volume. The concentration of insulin glargine in each of the experiments described below is 3.6378 mg/ml (corresponds to 100 units/ml). A second preparation is produced identically, but a specific amount of a surfactant is additionally added. The solutions are filled into 10 ml glass vessels (vials) and fitted with crimp caps. These vessels are now exposed to simulated in use or physicomechanical stress conditions:
1. In use test: The vessels are sorted into boxes with turned-up lids and stored during the investigation period of 28 days at +25� C. and controlled room humidity with exclusion of light. To simulate taking by the patient, once daily about 5 IU of the solutions are withdrawn using a customary insulin syringe and discarded. At the beginning and end of the working week this procedure is carried out twice in order to to simulate taking at the weekend. Before each withdrawal, visual assessment of the solution in the vessels for turbidity and/or particle formation is carried out. 2. Shaking test: The vessels are placed in a box with a turned-up lid lying on a laboratory shaker having an incubator and thermostat and shaken at 25� C. with 90 movements/min parallel to the horizontal movement for a period of time of 10 days. After defined times, the turbidity value of the samples is determined by means of a laboratory turbidity photometer (nephelometer) in formaldazine nephelometric units (formaldazine nephelometric unit=FNU). The turbidity value corresponds to the intensity of the scattered radiation of the light incident on suspended particles in the sample. Example 1
Stabilization of the in Use Period of Insulin Glargine Using Polysorbate 20 (Tween� 20)
a) The solution is sterile-filtered through a combination of 0.2 μm and 0.1 μm filters. It is then poured into 10 ml injection vials and sealed using crimp caps having an inserted sealing disk.
b) A comparison solution is prepared identically, but first a suitable amount of surfactant (10-30 ppm of polysorbate 20) is suspended in water for injection. The samples are stored at +5� C., 25� C. and 37� C. for a fixed period of time. 10 samples in each case are then subjected to an in use test. The results are shown in the table below.
Storage for 3 Months at 5� C.
Number of vials with particle formation after Test sample 7 days 14 days 21 days 28 days Insulin glargine 7 10 10 10 Insulin glargine + 0.010 mg/ml 0 0 0 0 of polysorbate 20 Insulin glargine + 0.015 mg/ml 0 0 0 0 of polysorbate 20 Insulin glargine + 0.020 mg/ml 0 0 0 1 of polysorbate 20 Insulin glargine + 0.030 mg/ml 0 0 0 0 of polysorbate 20 storage for 6 months at 5� C.
Number of vials with particle formation after Test sample 7 days 14 days 21 days 28 days Insulin glargine 1 10 10 10 Insulin glargine + 0.010 mg/ml 0 0 0 1 of polysorbate 20 Insulin glargine + 0.015 mg/ml 0 0 0 0 of polysorbate 20 Insulin glargine + 0.020 mg/ml 0 0 0 1 of polysorbate 20 Insulin glargine + 0.030 mg/ml 0 0 1 0 of polysorbate 20 Storage for 3 Months at 25� C.
Number of vials with particle formation after Test sample 7 days 14 days 21 days 28 days Insulin glargine 9 10 10 10 Insulin glargine + 0.010 mg/ml 2 2 2 2 of polysorbate 20 Insulin glargine + 0.015 mg/ml 0 0 0 1 of polysorbate 20 Insulin glargine + 0.020 mg/ml 0 0 0 0 of polysorbate 20 Insulin glargine + 0.030 mg/ml 0 0 0 0 of polysorbate 20 Storage for 6 Months at 25� C.
Number of vials with particle formation after Test sample 7 days 14 days 21 days 28 days Insulin glargine 10 10 10 10 Insulin glargine + 0.010 mg/ml 0 0 0 1 of polysorbate 20 Insulin glargine + 0.015 mg/ml 0 0 1 0 of polysorbate 20 Insulin glargine + 0.020 mg/ml 0 0 0 0 of polysorbate 20 Insulin glargine + 0.030 mg/ml 0 0 0 0 of polysorbate 20 Storage for 1 Month at 37� C.
Number of vials with particle formation after Test sample 7 days 14 days 21 days 28 days Insulin glargine 0 10 10 10 Insulin glargine + 0.010 mg/ml 0 3 3 5 of polysorbate 20 Insulin glargine + 0.015 mg/ml 0 0 0 0 of polysorbate 20 Insulin glargine + 0.020 mg/ml 0 0 0 0 of polysorbate 20 Insulin glargine + 0.030 mg/ml 0 0 0 0 of polysorbate 20 Storage for 3 Months at 37� C.
Number of vials with particle formation after Test sample 7 days 14 days 21 days 28 days Insulin glargine 5 9 10 10 Insulin glargine + 0.010 mg/ml 1 1 1 1 of polysorbate 20 Insulin glargine + 0.015 mg/ml 0 0 0 0 of polysorbate 20 Insulin glargine + 0.020 mg/ml 0 0 0 0 of polysorbate 20 Insulin glargine + 0.030 mg/ml 0 0 0 0 of polysorbate 20 Storage for 6 Months at 37� C.
Number of vials with
particle formation after
Insulin glargine + 0.010 mg/ml
of polysorbate 20
Insulin glargine + 0.015 mg/ml
Insulin glargine + 0.020 mg/ml
Insulin glargine + 0.030 mg/ml
Without addition of polysorbate 20, particle formation can occur in the solution even after 7 days in use. By addition of polysorbate 20, the particle formation can be markedly suppressed during the in use period.
The stabilizing action of polysorbate 20 is retained even on storage at elevated temperatures for a period of 3 months.
Stabilization of Insulin Glargine Using Polysorbate 20 Ander Physico-Mechanical Stress Loading
b) A comparison solution is prepared identically, but first a suitable amount of surfactant (0.010-0.030 mg/ml of polysorbate 20) is suspended in water for injection.
The samples are stored at +5� C., 25� C. and 37� C. for a fixed period of time. 5 samples in each case are then subjected to a shaking test. The results are shown in the table below, the limit 15 FNU corresponds to turbidities which are discernible in daylight.
Storage for 1 Month at 5� C.
Number of vials > 15 FNU 0 0.5 1 2 3 4 6 8 10 Test sample days days day days days days days days days Insulin glargine 0 0 0 2 3 3 4 4 4 Insulin glargine + 0.010 mg/ml 0 0 0 0 0 1 3 4 5 of polysorbate 20 Insulin glargine + 0.015 mg/ml 0 0 0 0 0 0 0 0 0 of polysorbate 20 Insulin glargine + 0.020 mg/ml 0 0 0 0 0 0 0 0 0 of polysorbate 20 Insulin glargine + 0.030 mg/ml 0 0 0 0 0 0 0 0 0 of polysorbate 20 Storage for 1 Month at 25� C.
Number of vials > 15 FNU 0 0.5 1 2 3 4 6 8 10 Test sample days days day days days days days days days Insulin glargine 0 0 0 1 1 1 1 2 3 Insulin glargine + 0.010 mg/ml 0 0 0 0 0 0 1 2 3 of polysorbate 20 Insulin glargine + 0.015 mg/ml 0 0 0 0 0 0 0 0 0 of polysorbate 20 Insulin glargine + 0.020 mg/ml 0 0 0 0 0 0 0 0 0 of polysorbate 20 Insulin glargine + 0.030 mg/ml 0 0 0 0 0 0 0 0 0 of polysorbate 20 Storage for 1 Month at 37� C.
Without addition of polysorbate 20, even after 2 days of severe physicomechanical stress, a visible turbidity can occur in the solution. By addition of polysorbate 20, the formation of turbidity during physicomechanical stressing can be markedly delayed. The stabilizing action of polysorbate 20 is retained even on storage at elevated temperatures.
Comparison of the Stabilization of the in Use Period of Insulin Glargine Using Polysorbate 20 (Tween� 20) and Using Polysorbate 80 (Tween� 20)
Open 10 vials in each case to give 5 ml of insulin glargine injection solution and
a) addition of 0.001 mg/ml of polysorbate 20 b) addition of 0.01 mg/ml of polysorbate 20 c) addition of 0.001 mg/ml of polysorbate 80 d) addition of 0.01 mg/ml of polysorbate 80
in the form of a concentrated stock solution.
Vials with particle
formation after
Insulin glargine +
0.010 mg/ml
of polysorbate 80
An addition of polysorbate 20 or of polysorbate 80 in a concentration of 0.001 mg/ml are equally able to stabilize the solution against particle formation during the in use period.
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