text:
Featured Courses
What's My Return Address? A Close Reading Strategy
This 2-hour professional development module is a dynamite close reading strategy that allows students to engage with informational texts, primary and secondary sources. It will inspire students to be decision-makers as they develop unique thought and thesis statements. They will engage with sources in new and thoughtful ways that will meet the higher cognitive demand of the Common Core Standards! The course contains an instructional video, slideshow, supporting materials and an assignment.
Social Studies Instruction with Sherlock Holmes
This 2-hour professional development module allows history and social studies teachers to crystallize their planning by using quotes from the world's most famous detective as their guide. Sherlock Holmes walks through 7 rules of effective planning and instruction as educators more effectively define what they want their students to know and what they should be able to do - as well as integrate effective instructional techniques and technology.
The course contains a slideshow, video, google form assignment document and supporting materials.
Social Studies can be SPECtacular: A Close Reading and Writing Strategy
This 2-hour professional learning module will allow English/ Language Arts and History/ Social Studies educators to engage with informational text utilizing a close reading strategy. The module contains an instructional video, slideshow and an assignment that connects educators to a Common Core exemplar text as well as another source that showws different treatment of the same topic by different author and through a different medium.
There will also be a link to a forum where the conversation and collaboration can continue in order to make this strategy evlove to mee the needs of your classroom.
Creating a Top-Notch Online Mini-Course
This course will highlight the key elements of creating a mini-course on Teachers Train Teachers. It contains a slideshow, an online survey to capture the key elements of creating and marketing a mini-course, a video explaining the key elements of creating a mini-course, and a supplementary powerpoint for download.
Participants will engage with the technical components of creating the mini-course as well as:, creating engaging course descriptions, embedding materials such as slideshows, videos, quizzes and surveys, marketing their course through the Professional Learning Networks, andpricing their course appropriately
This course meets the requirements of many educator effectiveness instruments; particularly in the domains and standards that reference professional learning, contributing to the profession and seeking out targeted professional development opportunities.


text:
ST PETERSBURG, Russia (Reuters) - Concerns about China and Russia are overblown and offer investors a chance to buy into booming growth stories, Jim O'Neill, chairman of Goldman Sachs Asset Management, said on Friday.
O'Neill, who coined the BRIC term in 2001 to describe how the clout of Brazil, Russia, India and China would challenge the West's economic dominance, said jitters about such markets were overblown given such swift growth forecasts for the next decade.
"For those who have a little bit of foresight, it gives them the chance to get in at sensible levels," O'Neill, who helps oversee $677 billion in assets at Goldman, told Reuters Insider television at the St Petersburg Economic Forum in Russia.
"China and Russia are both looking quite interesting because they are cheap," he said. "Contrary to the email I get every two hours about why I should drop the R from BRIC, I quite like Russia."
Anxiety about a U.S. slowdown and inflation in China have prompted the likes of U.S. market strategist Richard Bernstein to talk of "monstrous" risks to emerging markets.
O'Neill said the short-term worries about the BRICs did not undermine the attractive long-term growth story.
"The long-term trend is for the BRIC economies and the BRIC investment theme to continue to be the dominant themes of our generation," he said.
He said that apart from Russia, his other top pick was financial stocks in developed countries, though he declined to name specific stocks.
But O'Neill did say the future of China -- and inflation in particular -- was the one issue that kept him awake at night.
"If this view that is growing, particularly in the (United) States, that China is already going down the hard landing path, that would be a big deal ... I think China is slowing because the authorities are deliberately trying to slow it," he said.
"As soon as we see the slightest sign of inflation starting to turn around, the markets will stop worrying about more tightening," he said.
O'Neill said China, Russia, Brazil and India would collectively have economies bigger than the U.S. economy by the end of this decade and this would have a big impact on who runs financial institutions such as the International Monetary Fund.
He said he thought the slowdown in U.S. growth was temporary but, if it was not, investors should expect a third round of quantitative easing, or QE3 -- a term that describes treasury bond purchases by the central bank to stimulate the flow of credit and investment.
"I am a bit surprised and confused by the evidence that the U.S. has slowed so much. I still suspect it is only temporary and might have something to do with the Japanese supply disruption. If I am wrong then we will get QE3, though it might not be described that way," he said.
Writing by Guy Faulconbridge, editing by Timothy Heritage

subset: commoncrawl


text:
July 15, 2014
Listening to What Voice of Customer Research Has to Tell You
Voice of customer research is going to help identify the top priority needs and wants of your clients. You're getting the information you need through interviews, focus groups, surveys and so on, right from the source. Rather than speculating about how to continue meeting the needs of your clients, you can gather the information yourself to get a better idea of where you need to be heading in the future.
What you can do with that feedback
Every brand has an idea of the type of interaction they're hoping for with clients and consumers in general. Even if you never sit down and fill in the details about what that would look like, there are a few components that are pretty universal.
You hope that it's a positive interaction with top-notch customer service. The client is pleased with the product or service. All good things! But here's the thing: The way you perceive your interactions is going to differ with the actual customer experience. It doesn't mean that all of your clients are secretly dissatisfied, just that it's better to check in and get the details about what they're liking and not so fond of, instead of making assumptions.
A lot of brands engage in some form of voice of customer research. There are handy little surveys and polls, interviews, and many other ways to hear from customers. What matters is what brands are doing once they're given a peek into the average customer experience. Too often, it's collected and then mostly ignored, or under-utilized.
It's actually a great resource if you're trying to look ahead and determine where your brand's headed. Who better to give you a sense of what needs to change than the people who are most familiar with what you do?
Too many times, brands make changes for the sake of change, rather than understanding what users are asking for and need. What your brand does with feedback can have a lot to do with successes and failures down the road. Brands that stick around and accomplish great things tend to be the ones who understand that change needs to happen in a way that makes sense to customers. It means looking at feedback about feature updates, customer service, and other aspects of what you do to see where change is needed most.
The great thing about voice of customer research is that it gives you the insight to head in the direction that'll keep you competitive and able to please customers. The key is making the choice to invest and truly listen and act on what's being said.


text:
By ED WHITE, Associated Press – 20 mins agoSANDUSKY, Mich. – A Cessna airplane touched down about midnight, dropped a load of drugs and was back in the air in 90 seconds. Suddenly, the pilot of a U.S. border patrol helicopter hovering nearby turned on a powerful spotlight and tracked an SUV fleeing with hockey bags stuffed with 175 pounds of marijuana and 400,000 Ecstasy-type pillsread the articlehttp://news.yahoo.com/s/ap/20110515/ap_ … nes_borderlooks like Canadian drug dealers are taking advantage of remote, small airports to make drop offs of drugs...
oh, the lengths we go to to make sure that people don't have fun and kill themselves...what a waste of my money.
We need to build a wall and place some AAA at the border. That'll stop those damned Canuck pot heads!
Copyright © 2017 HubPages Inc. and respective owners.
Other product and company names shown may be trademarks of their respective owners.
HubPages® is a registered Service Mark of HubPages, Inc.
HubPages and Hubbers (authors) may earn revenue on this page based on affiliate relationships and advertisements with partners including Amazon, Google, and others.
terms of use privacy policy (0.31 sec)


text: Practical, understandable, and evidence-based, this book introduces the most common medical emergencies that dental professionals may encounter in clinical practice. Etiology, signs, symptoms, and treatment for each emergency are presented in a clear and logical format that promotes learning and allows for quick reference. Additionally, the book stresses emergency prevention and preparedness by highlighting the importance of the medical history, vital signs, and the development of a medical emergency kit. Special features that make this book an excellent tool for clinicians include: case scenarios, signs and symptoms tables, and treatment flow charts.


text:
Whatever, lol, Brady will probably pull a win out of his asshole like usual.
We were just talking about this at lunch.
It should be close (unless one team just doesn't show up for whatever reason) and Flaco turns it on this time of year, and isn't intimidated by the Pats at all.
I think the Pats will drop this game, and the Denver game, limp into the playoffs uninspired and lose to the Ravens at home after the bye in the playoffs, just like a couple years ago.
I think Bill lost the team, and unless the D suddenly comes alive again… They don't have a shot.
Well, I certainly like your prediction!
I do think it'll be pretty close and the Raven's D is pretty good this year, but they haven't faced a really good qb in a while. They better pass rush better than they have been.
Don't have to do that to beat the Pats this year. Just enough pressure to get Brady moving will work, his knee is FUBAR.
Also, with GRonk out, you cover Edellman and Bennet, stop Blunt and force Brady to win with the Rookie and the white guy from the Dolphins with intermediate range passes. He can't.
So, Playoff predictions:
I'm really torn on the AFC North, but I'm leaning towards the Steelers. The Raven's have such a tough remaining schedule, but I think they can hold out enough to get that 6 seed.
They have the #2 scoring defense this year. I don't see them losing this one at home.
Sure they play bend but don't break, and are much better in the last 30 yards than the first 70.
But you have to understand my perspective. This D was supposed to be elite, like #1, better than Seattle etc coming into this year. Then outside of last week they have just played real base zone D and have been picked apart...
They have only played two good offenses this year, to your point (Seattle, Pittsburgh) but they are also top ten in yards. Also, their offense is 6 in points scored and they rarely lose at home. Still a damn good team. AFC will be going through Foxborough this year.
BTW, who is your team Beans?
He's a self-deprecating Pats fan, lol...
I just hope Brady doesn't pull some deflategate bullshit, right @countingbeans :badpokerface:
Damn, haha, I thought I was harsh on my team. I guess when you have 4 Superbowls in the last 15 years, you have higher standards than the rest of us.
Ravens always play the Pats tough though, so should be a good game.
They might as well put an ad on Craigslist for a new Rams coach. Piece of shit team, all the hoopla because it came back to LA, all for nothing.
Sweet game
Wouldn't have even been close had the Pat's special teams not went full retard there for 2 plays
I'll be honest, D looked like a pack of studs out there. Made Flacco look very, very human, and were pounding on people.
Offense looked great against a damn good Ravens D.
And the Pats played well enough to overcome awful SP meltdown in the third.
That rookie RB for the Ravens is a tough mofo.
Tom is the greatest.
The pre-game story about the kid with terminal brain cancer who loves/admires Brady so much he had his neurosurgeon carve Brady's jersey number into his skull at the time of his last surgery--man, that story was a tearjerker.
Finally got the chance to watch it yesterday, while on a client site, waiting for the owner to come back from lunch.
I had tears flowing hardcore when the client came back. He's like "ummmm, everything alright"
"Have you seen this story here?" And I pointed to the video.
He was like "ohhh, yeah, I cried when I saw that the other night too."
Looks like I should eat some shit on the Pats D. I guess it's better than I thought.
Outside the two touches they handed Baltimore with crap ST play... They have been lights out for a couple weeks now.


text:
What does a coffee cup mean to you?
from our Sunday reading series - a weekly blog post (subscribe here)
In a recent trip to my alma mater in the Southern USA, I had a welcome surprise imeeting the students who currently sit on the Environmental Concerns Committee. This was significant as I was one of the ECC's Co-Founders back in the mid-90s. It was my first experience of being in a partnership, from a leadership perspective, as well as learning to delegate to a committee. Our results included a recycling programme which spread across the campus and a 'Green Team' welcome committee that recycled copious amounts of cardboard at the beginning of each school year. It turns out that the ECC is still going strong today, approximately twenty years after its genesis.
It was delightful to talk about the "3 Rs" with folks who understand the concept inside and out. And for your own reference, the 3 Rs, often shown in the form of green arrows going around in a triangular pattern, are in order of priority: Reduce – Reuse – Recycle.
The result of the work we did meant that environmental responsibility became core to our beings. So when I took my first job as a retail manager in London, I immediately jumped on board as Environmental Coordinator for the shop. A few years later, when an artist friend received ERDF funding (European Regional Developmental Fund, which will not be available in the UK post-Brexit) for doing eco-audits of small businesses, my art consultancy was fully assessed, advised and given official status as an environmentally sound enterprise.
And so, during the recent trip to the USA, a travel companion stands out: a black and blue reusable coffee cup. The make is a Keep Cup, and readers who have either met with me on a one-to-one basis or seen me on stage might very well have spotted it. The thing is that it goes almost everywhere with me, from airplanes to studios, and from coffee shops to lecture halls. As great as the Keep Cup is at being pleasant to use, keeping coffee or tea warm and preventing liquid from spilling (noting its effective lid), it equally reminds others of environmental mindfulness. People see my example of taking around a reusable cup that looks nice, works well and saves trees (the latter being the first 'r', reduce), and realise that this is something they could do, too.
What does the Keep Cup have to do with business? It represents a core value. If my business has an 'environmental policy' (which it does), it's important that the founder is being true to it, when working and playing. Moreover, it's a great way to demonstrate the kind of values upheld. This sort of behaviour stands out to others, which can help people connect with you, have increased interest and even trust in your work and, you never know, might even inspire others to do the same.
What core values can you demonstrate in your day to day life? While it might not be something that you've noticed others doing, it might be something that you can do to be true to yourself, show what you value and stand out from the crowd.
Not yet on the mailing list? Come on board and receive pearls of wisdom directly into your inbox!
This includes our weekly Sunday reading blog and tips that are only available to email subscribers.
Want to understand best practices in the arts? How about honing your speaking skills or learning about funding opportunities?
The Creative Specialists Programme is here to support you with a team of expert advisors ready to divulge knowlege.
Check out the Creative Specialists Programme OR Register your interest now (we'll send you full details): email@example.com


text:
The 2010 vintage was Henry Kotzé's first at Morgenster in Somerset West after his move from Eikendal and the farm's two Bordeaux-style reds from that year have just been released.
The Lourens River Valley 2010 is a blend of 50% Cabernet Franc, 33% Merlot, 10% Cabernet Sauvignon and 7% Petit Verdot and was matured for 16 months in French oak, 30% new (price: R149). It seems designed to have the broadest possible appeal – very expressive on the nose with plenty of red berries and some attractive oak spice while the palate is fruit driven with fresh acidity and fine tannins. Sweet and juicy upfront before a savoury finish. Score: 16.5/20.
The Morgenster 2010, however, is in a different league. A blend of 48% Merlot, 25% Cabernet Sauvignon, 20% Cabernet Franc and 7% Petit Verdot, it spent 18 months in French oak, 60% new (price: R320). I think Kotzé is inclined to pursue plushness rather than austerity but he does this in a very accomplished manner. There's plenty of fruit concentration but great structure, too – there's grip but these tannins are not at all coarse or hard. Red and black fruit and subtle vanilla but also hints of more savoury notes like mixed herbs and olive. Dense but not weighty and seamlessly put together. Ridiculously easy to drink now but should improve at least until 2017. Score: 18/20.
Also on show yesterday was the Morgenster White 2012. The second vintage of a Bordeaux-style white from Kotzé, it's made from bought-in grapes and consists of 53% Semillon and 47% Sauvignon Blanc and matured in French oak for eight months, 25% new (price: R149). It's subtle and restrained, which are normally admirable qualities, but this a difficult wine to get to grips with. Really applying myself, I found green melon, white peach and a touch of vanilla. I think it will be better in twelve months' time so a score of 16/20.
Tagged Henry Kotzé, Lourens River Valley, Morgenster
Drinking the LRV 2007 and quite pleasantly surprised by its longevity, and certainly – its qualities in a typical Morgenster style – this was not an easy / promising vintage i believe .. Cannot wait to sample and buy the 2010 – need cases of fine and affordable Bordeaux in my fast depleting cellar
I was lucky enough to join a vertical tasting this morning with Mr Bertrand, Pierre Lurton, Henry, Bob our viticulturist and the sales team. We tasted LRV 1998 – 2012 as well as Morgenster 2000 – 2012 (2002 and 2007 no MS was produced). The overall opinion was the incredible age ability of the wine
Tasted the Morgenster 2001 last year, brought a bottle and opened 3 weeks ago. Also Merlot dominated (51%), still refined and extremely drinkable. Platter (2005 ed) mentions keeping for 5+ years, but still going strong after 12 yrs!


text:
Corporate Reputation Decoded is the first book of its kind that traces the journey of Indian companies in building corporate reputation (CR). The book addresses CR in the Indian context and is in response to the growing interest of companies in this area. The book explains the process of building, maintaining and strategizing for CR. It also discusses various aspects of CR company's stakeholders, situations demanding CR interventions and the impact of a company's culture, ethics and leadership on its CR. The book expounds on these using Indian cases (Tata, Infosys, HUL, Reliance, Aditya Birla Group, HDFC, among others), which enhance the understanding of CR in India as well as benchmark CR best practices in India. The book is of major significance to CR practitioners, scholars, teachers, students and C-Suite professionals who will also find the techniques proposed in the book interesting as they can assess, evaluate, adopt and adapt strategies followed by other companies for reputation enhancement.
"The authors demystify the complex process of building a corporate reputation in a comprehensive yet simplistic and easily understandable framework, drawing largely upon the journey of Indian corporates. The four critical factors for strategic structuring of reputation outlined in the book, viz., economic logic; goals and objectives; values, vision and mission and environment, appear analogous to the four movements of an orchestral symphony and align the theme of the book. A must-read for every organisation and leader targeting corporate excellence."
(N. K. Maini)
"A remarkably practical, lucid and well-researched book complete with examples, framework and strategies from corporations in India for building corporate reputation, invaluable for any corporate executive concerned with the subject of building corporate reputation."
(Dr Arvind N. Agrawal)
"Decoding the DNA of the corporate reputation gene, more so in the Indian context, is a new path to discovery that the authors have commendably embarked upon. When corporates make larger societal value creation a core raison d'être and this commitment drives the enterprise mind, body and spirit, it can unleash a virtuous cycle of innovation and excellence for sustainable competitive advantage. Reputational assets are then a natural outcome."
(Nazeeb Arif)
"Reputation of a corporate house cannot be built overnight. It takes years of sustained efforts to perpetually meet the expectations of various stakeholders, particularly customers, by instilling a deep-rooted culture of ethical business practices. Interestingly, like various other dimensions of a business, reputation can also be strategised, nurtured and developed for the gainful dividend. Corporate Reputation Decoded is an excellent practical handbook in this regard."
(Sudhir Vasudeva)
About the Author
Asha Kaul is Professor in the Communication Area, Indian Institute of Management, Ahmedabad. She obtained her doctorate in stylistics from the Indian Institute of Technology, Kanpur in 1990. She is the author of Effective Business Communication (2000), The Effective Presentation: Talk Your Way to Success (2005), Business Communication (2nd edition, 2009) and is the co-editor of two books: Management Communication: Trends and Strategies (2006) and New Paradigms for Gender Inclusivity (2013).
Her current areas of interest include genderlect, politeness, managerial, corporate and digital communication. Currently she is working on Indian cases to comprehend the intricacies involved in corporate decision making for enhancing reputation.
Her areas of interest are investor relations, corporate reputation and corporate communication, especially financial communication.


text:
|Publication number
|Publication type
|Application number
|Publication date
|Nov 2, 2010
|Filing date
|Feb 22, 2002
|Priority date
|Feb 23, 2001
|Fee status
|Also published as
|Publication number
|Jeffrey L. Cleland, Franklin Okumu
|Original Assignee
|Genentech, Inc.
|Export Citation
|BiBTeX, EndNote, RefMan
|Patent Citations (71), Non-Patent Citations (18), Referenced by (4), Classifications (17), Legal Events (2)
|External Links: USPTO, USPTO Assignment, Espacenet
This application claims the benefit of U.S. Provisional Application No. 60/270,845, filed Feb. 23, 2001, which is incorporated herein by reference.
Controlled delivery of beneficial agents, especially peptide- and protein-based drug therapies, can be achieved through the use of bioerodible polymeric implants. Traditionally, this technology has involved surgical implantation of a polymeric monolith containing a suspended beneficial agent. Examples of these monoliths are described in U.S. Pat. Nos. 6,110,503, 6,051,259, and 6,146,662. Certain complex shapes and/or formulations of these monoliths have been developed to provide specific rates of release of the beneficial agent over a period of time. A drawback to this implantation approach is the need to perform an incision in the patient in order to place the implant.
In order to eliminate the need for surgical implantation, implants have been developed which can be administered by the injection of a viscous composition. Compositions for injection must have a sufficient ability to flow so that the implant can pass through a syringe and needle. However, these formulations should not simply dissipate into the body but rather should form a discrete depot from which the drug is released. Typically, the composition transforms into a solid or a gel upon encountering the aqueous environment within an organism.
To accomplish this balance of physical properties, various formulations of bioerodible polymers, biocompatible solvents, beneficial agents, and other ingredients have been employed. Release of the beneficial agent from the polymeric matrix of the implant can then occur by: diffusion of the agent from the matrix; by degradation of the polymer and subsequent release of the agent into the surrounding environment; or by a combination of these two mechanisms.
One approach to the formulation of injectable compositions has been the use of solvents which are miscible or dispersible with water (hydrophilic solvents). For example, U.S. Pat. No. 6,143,314 describes injectable compositions containing poly(lactic acid-co-glycolic acid) (PLGA) and a hydrophilic solvent such as dimethyl sulfoxide (DMSO) or N-methyl pyrrolidone (NMP). U.S. Pat. Nos. 5,278,201 and 4,938,763 describe poly(lactic acid), poly(glycolic acid), and their copolymers combined with NMP and a beneficial agent to form injectable liquid compositions. Depots of these same polymers also can be formed by injecting a composition containing a prepolymer, which then forms the polymer during the implantation process. As described in U.S. Pat. Nos. 5,340,849 and 5,278,202, compositions of NMP, a beneficial agent, and polymer precursors can form a polymer gel upon injection into an aqueous environment due to polymerization of the polymer precursors in the presence of water.
The beneficial agent can be either dissolved or dispersed in these formulations. Water-soluble beneficial agents, including peptides and proteins, are typically dissolved by the solvents which are miscible in aqueous body fluids. The solvents used in these compositions tend to provide for the rapid influx of water into the implant. This promotes rapid solidification of the polymer at the implant surface and promotes diffusion of the beneficial agent from the implant, often resulting in an initial, rapid release of the beneficial agent. This "burst" often results in the release of a substantial portion of the beneficial agent within a very short time. For example, 25-75% of the beneficial agent can be released within 24 hours of administration. In some cases, the burst can be followed by a drastic reduction in the release of the beneficial agent before a gradual release begins. This pause in the release behavior is referred to as a "lag time."
A burst effect and/or lag time can be unacceptable, particularly in circumstances where sustained delivery is desired. For example, it may be desirable to deliver the beneficial agent over a period of a week or a month or longer. To control release rates of these systems, it is often necessary to include additional ingredients which can moderate the release of the beneficial agent and/or control the porosity of the implant. For example, U.S. Pat. Nos. 5,599,552 and 5,487,897 describe complex compositions which use poly(D,L-lactic acid) to provide an implant that has a porous or liquid core surrounded by a layer, or "skin," of polymer. This morphology is reported to provide for a more uniform release rate. Release of a beneficial agent can also be controlled by complexing the agent to make it less soluble in water, as described in U.S. Pat. No. 5,780,044; however, complexation can affect the activity, and thus the efficacy, of the beneficial agent.
An alternative approach to the formulation of controlled release compositions has been the use of solvents which are immiscible with water. For example, U.S. Pat. No. 6,130,200 describes gels of PLGA and a water-immiscible (hydrophobic) solvent in which peptide-based drugs are suspended as particles. When administered, the gels have sufficient dimensional stability to form a cohesive depot. The hydrophobic solvent in these systems inhibits the rapid uptake of water, resulting in the reduction or elimination of any burst release. One drawback to this system is the high viscosities exhibited by the gels. Large diameter needles (16-gauge to 20-gauge) must be employed to administer the composition by injection, and high pressures are necessary for administration. This can be especially disadvantageous in the treatment of chronic conditions, such as the administration of insulin to diabetic patients. Another drawback is the tendency of the particulate beneficial agent to settle out of the composition over time. This instability can necessitate special storage conditions, short storage times, and/or special handling conditions during administration. If the beneficial agent settles out once the implant is in the organism, the rate of release of the agent over time can become unpredictable.
There is thus a need for compositions for the gradual release of a beneficial agent which can be easily administered by injection. These compositions will ideally exhibit controlled release of the agent, without unintended periods of rapid release or zero release. Additionally, stability for long periods of time and under various storage conditions would be desirable.
In a first aspect, the present invention is a composition for administration of a beneficial agent, containing: a solvent mixture including a hydrophobic solvent and a hydrophilic solvent; a bioerodible polymer; and a beneficial agent. The polymer and the beneficial agent are dissolved.
In a second aspect, the present invention is a composition for administration of a beneficial agent, containing: a solvent mixture including a hydrophobic solvent and a hydrophilic solvent; a bioerodible polymer; and a beneficial agent. The viscosity of the composition is less than 2000 centipoise.
In a third aspect, the present invention is a composition for administration of a beneficial agent, containing: a solvent mixture including a hydrophobic solvent and a hydrophilic solvent; a bioerodible polymer dissolved in the solvent mixture; and a beneficial agent dissolved in the solvent mixture. The viscosity of the composition is less than 2000 centipoise, at least 90 wt % of the solvent mixture is the hydrophobic solvent, the hydrophobic solvent has a solubility in water of less than 0.1 wt %, and less than 5% of the beneficial agent is released in 24 hours following administration in vivo.
In a fourth aspect, the present invention is a method of administering a beneficial agent, including injecting the above compositions into an organism through a needle.
In a fifth aspect, the present invention is a kit containing a container; a hydrophobic solvent; a hydrophilic solvent; a bioerodible polymer; and a beneficial agent. The amount of the hydrophobic solvent and the hydrophilic solvent is sufficient together to dissolve all of the polymer and the beneficial agent.
Various other objects, features and attendant advantages of the present invention will be more fully appreciated as the same becomes better understood from the following detailed description when considered in connection with the accompanying drawings in which like reference characters designate like or corresponding parts throughout the several views and wherein:
The present invention includes a solution of a bioerodible polymer dissolved in a mixed solvent system containing at least two solvents. The polymer solution is mixed with a beneficial agent to form a liquid or gel which can be injected into an organism, preferably using a needle having a diameter no greater than that of a 20-gauge needle. The beneficial agent is then slowly released from the composition into the organism. Compositions can be prepared and administered to provide for continual release of a beneficial agent over a period of time with minimal burst release upon injection. The compositions of the invention are especially useful for peptide- and protein-based beneficial agents. The solution of polymer in the solvent mixture preferably provides for stabilization of the beneficial agent during storage and during the release period.
The mixed solvent system dissolves both the polymer and the beneficial agent. Preferably, the composition is a solution, which means a liquid having multiple ingredients homogeneously distributed in a single phase. Alternatively, the composition may be an suspension of the beneficial agent. Both solutions and suspensions are contrasted with emulsions, which have more than one liquid phase.
It is preferred that the solvents in the solvent mixture exhibit different levels of solubility in water. The solvent which is less soluble in water is called the hydrophobic solvent, and the solvent which is more soluble in water is called the hydrophilic solvent.
Water solubility may be determined experimentally as follows: five grams of water are placed in a clear container at 20� C. and weighed, and a solvent is added dropwise. The solution is swirled to observe phase separation. When the saturation point appears to be reached, as determined by observation of phase separation, the solution is allowed to stand overnight and is checked again the following day. If the solution is still saturated, as determined by observation of phase separation, then the percent by weight of solvent added is determined. Otherwise more solvent is added and the process repeated. Solubility is determined by dividing the total weight of solvent added by the final weight of the solvent/water mixture.
Preferably the hydrophobic solvent accounts for more than half of the mass of the solvent mixture. Useful hydrophobic solvents exhibit a solubility in water less than 1 wt %, preferably less than 0.5 wt %, more preferably less than 0.1 wt %. Especially preferred are hydrophobic solvents having a solubility in water less than 0.05 wt %.
Examples of hydrophobic solvents include the alkyl and aralkyl esters of aryl acids such as benzoic acid, phthalic acid, and salicylic acid; alkyl esters of citric acid, such as triethyl citrate and tributyl citratrate; aryl, aralkyl and alkyl ketones and aldehydes; and mixtures thereof. Among preferred solvents are those having solubilities within the foregoing range selected from (i) compounds having the structural formulas: R1—C(═O)—O—R2 or R1—C(═O)—R2 in which R1 is aryl or aralkyl, R2 is alkyl or aralkyl, and R1 and R2 are optionally the same or different, with the proviso that when each of R1 and R2 are alkyl, the total carbon atoms in R1 and R2 combined are 4 or more, (ii) alkyl and aralkyl esters of phthalic acid, isophthalic acid and terephtalic acid, and (iii) alkyl and aralkyl esters of citric acid. Alkyl means straight, branched, or cyclic hydrocarbons having preferably 1-20 carbon atoms, optionally substituted with non-interfering substituents. Aralkyl means (alkyl)phenyl, for example benzyl, phenethyl, 1-phenylpropyl, and 2-phenylpropyl. Aryl means phenyl, optionally substituted by non-interfering substituents. Many of the solvents useful in the invention are available commercially (SIGMA/ALDRICH, Milwaukee, Wis.) or may be prepared by conventional esterification of the respective arylalkanoic acids using acid halides, and optionally esterification catalysts, such as described in U.S. Pat. No. 5,556,905, and in the case of ketones and aldehydes, by oxidation of their respective alcohol precursors.
Benzoic acid derivatives from which hydrophobic solvents may be selected include: 1,4-cyclohexane dimethanol dibenzoate, diethylene glycol dibenzoate, dipropylene glycol dibenzoate, polypropylene glycol dibenzoate, propylene glycol dibenzoate, diethylene glycol benzoate and dipropylene glycol benzoate blend, polyethylene glycol (200) dibenzoate, iso-decyl benzoate, neo-pentyl glycol dibenzoate, glyceryl tribenzoate, pentaerylthritol tetrabenzoate, cumylphenyl benzoate, trimethyl pentanediol dibenzoate.
Phthalic acid derivatives from which hydrophobic solvents may be selected include: Alkyl benzyl phthalate, bis-cumyl-phenyl isophthalate, dibutoxyethyl phthalate, dimethyl phthalate, diethyl phthalate, dibutyl phthalate, diisobutyl phthalate, diisoheptyl phthalate, butyl octylphthalate, diisonoyl phthalate, nonyl undecylphthalate, dioctyl phthalate, di-isooctylphthalate, dicapryl phthalate, mixed alcohol phthalate, di-(2-ethylhexyl) phthalate, linear heptyl nonylphthalate, linear heptyl nonyl undecyl phthalate, linear nonyl phthalate, linear nonyl undecylphthalate, linear dinonyl didecylphthalate, diisodecyl phthalate, diundecyl phthalate, ditridecyl phthalate, undecyidodecyl phthalate, decyltridecyl phthalate, 1:1 blend of dioctyl and didecyl phthalates, butyl benzyl phthalate, and dicyclohexyl phthalate.
Preferred hydrophobic solvents include the alkyl and aralkyl esters of the aryl acids described above. Examples of acids are benzoic acid and the phthalic acids, such as phthalic acid, isophthalic acid, and terephathalic acid. Most preferred solvents are derivatives of benzoic acid and include, for example, methyl benzoate, ethyl benzoate, n-propyl benzoate, isopropyl benzoate, butyl benzoate, isobutyl benzoate, sec-butyl benzoate, tert-butyl benzoate, isoamyl benzoate and benzyl benzoate, with benzyl benzoate being most especially preferred. Furthermore, mixtures of any of the hydrophobic solvents may also be used.
Hydrophilic solvents useful in solvent mixtures are those solvents that are miscible with the hydrophobic solvent and include, for example benzyl alcohol, methanol, 1-butanol, t-butanol, triacetin, diacetin, tributyrin, triethyl citrate, tributyl citrate, acetyl triethyl citrate, acetyl tributyl citrate, triethylglycerides, triethyl phosphate, diethyl phthalate, diethyl tartrate, mineral oil, polybutene, silicone fluid, glycerin, ethylene glycol, polyethylene glycol, octanol, ethyl lactate, propylene glycol, propylene carbonate, ethylene carbonate, butyrolactone, ethylene oxide, propylene oxide, N-methyl-2-pyrrolidone, 2-pyrrolidone, glycerol formal, methyl acetate, ethyl acetate, methyl ethyl ketone, dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, caprolactam, decylmethylsulfoxide, oleic acid, 1-dodecylazacycloheptan-2-one, and mixtures thereof.
A useful hydrophilic solvent exhibits a solubility in water greater than the hydrophobic solvent with which it is mixed, typically between 1 wt % and up to and including miscibility with water, preferably up to and including 50 wt %, and most preferably up to and including 25 wt %. Especially preferred are hydrophilic solvents having a solubility in water from 2 wt % to 10 wt %.
The solvent mixture may contain more than two solvents. For example, the solvent mixture may contain two or more hydrophobic solvents, two or more hydrophilic solvents, and/or one or more solvents exhibiting a solubility in water which is between those of the specific hydrophilic and hydrophobic solvents. It is preferred that the total amount of solvent or solvents having a solubility in water of less than 1 wt % accounts for at least 55 wt % of the solvent mixture, preferably at least 75 wt % of the mixture, more preferably at least 90 wt % of the solvent mixture.
The polymers for use with the present invention are materials which decompose when placed inside an organism. Bioerodible polymers eliminate the need to remove the implant after the beneficial agent has been released, since the polymer will gradually break down and may be metabolized or excreted from the body. This decomposition can be observed as a decline in the molecular weight of the polymer over time. Polymer molecular weights can be determined by a variety of methods including size exclusion chromatography (SEC), and are generally expressed as weight averages or number averages. A polymer is bioerodible if, when in phosphate buffered saline (PBS) of pH 7.4 and a temperature of 37� C., its weight-average molecular weight is reduced by at least 25% over a period of 6 months as measured by SEC.
Bioerodible polymers which are useful for the present invention include polyesters, such as poly(caprolactone), poly(glycolic acid), poly(lactic acid), and poly(hydroxybutryate); polyanhydrides, such as poly(adipic anhydride) and poly(maleic anhydride); polydioxanone; polyamines; polyamides; polyurethanes; polyesteramides; polyorthoesters; polyacetals; polyketals; polycarbonates; polyorthocarbonates; polyphosphazenes; poly(malic acid); poly(amino acids); polyvinylpyrrolidone; poly(methyl vinyl ether); poly(alkylene oxalate); poly(alkylene succinate); polyhydroxycellulose; chitin; chitosan; and copolymers and mixtures thereof.
The beneficial agent can be any physiologically or pharmacologically active substance or substances optionally in combination with pharmaceutically acceptable carriers and additional ingredients such as antioxidants, stabilizing agents, etc. that do not substantially adversely affect the advantageous results that may be attained from administration of the beneficial agent. The beneficial agent may be any of the agents which are known to be delivered to the body of a human or an animal. These agents include drug agents, medicaments, vitamins, and nutrients. Included among the types of agents which meet this description are lower molecular weight compounds, proteins, peptides, genetic material, nutrients, vitamins, food supplements, sex sterilants, fertility inhibitors and fertility promoters.
Drug agents which may be delivered by the present invention include drugs which act on the peripheral nerves, adrenergic receptors, cholinergic receptors, the skeletal muscles, the cardiovascular system, smooth muscles, the blood circulatory system, synoptic sites, neuroeffector junctional sites, endocrine and hormone systems, the immunological system, the reproductive system, the skeletal system, autacoid systems, the alimentary and excretory systems, the histamine system and the central nervous system. Suitable agents may be selected from, for example, proteins, enzymes, hormones, polynucleotides, nucleoproteins, polysaccharides, glycoproteins, lipoproteins, polypeptides, steroids, analgesics, local anesthetics, antibiotic agents, anti-inflammatory corticosteroids, ocular drugs and synthetic analogs of these species.
Examples of drugs which may be delivered by the composition of the present invention include, prochlorperzine edisylate, ferrous sulfate, aminocaproic acid, mecamylamine hydrochloride, procainamide hydrochloride, amphetamine sulfate, methamphetamine hydrochloride, benzamphetamine hydrochloride, isoproterenol sulfate, phenmetrazine hydrochloride, bethanechol chloride, methacholine chloride, pilocarpine hydrochloride, atropine sulfate, scopolamine bromide, isopropamide iodide, tridihexethyl chloride, phenformin hydrochloride, methylphenidate hydrochloride, theophylline cholinate, cephalexin hydrochloride, diphenidol, meclizine hydrochloride, prochlorperazine maleate, phenoxybenzamine, thiethylperzine maleate, anisindone, diphenadione erythrityl tetranitrate, digoxin, isoflurophate, acetazolamide, methazolamide, bendroflumethiazide, chloropromaide, tolazamide, chlormadinone acetate, phenaglycodol, allopurinol, aluminum aspirin, methotrexate, acetyl sulfisoxazole, erythromycin, hydrocortisone, hydrocorticosterone acetate, cortisone acetate, dexamethasone and its derivatives such as betamethasone, triamcinolone, methyltestosterone, 17-S-estradiol, ethinyl estradiol, ethinyl estradiol 3-methyl ether, prednisolone, 17-α-hydroxyprogesterone acetate, 19-norprogesterone, norgestrel, norethindrone, norethisterone, norethiederone, progesterone, norgesterone, norethynodrel, aspirin, indomethacin, naproxen, fenoprofen, sulindac, indoprofen, nitroglycerin, isosorbide dinitrate, propranolol, timolol, atenolol, alprenolol, cimetidine, clonidine, imipramine, levodopa, chlorpromazine, methyldopa, dihydroxyphenylalanine, theophylline, calcium gluconate, ketoprofen, ibuprofen, cephalexin, erythromycin, haloperidol, zomepirac, ferrous lactate, vincamine, diazepam, phenoxybenzamine, diltiazem, milrinone, mandol, quanbenz, hydrochlorothiazide, ranitidine, flurbiprofen, fenufen, fluprofen, tolmetin, alclofenac, mefenamic, flufenamic, difuinal, nimodipine, nitrendipine, nisoldipine, nicardipine, felodipine, lidoflazine, tiapamil, gallopamil, amlodipine, mioflazine, lisinolpril, enalapril, enalaprilat captopril, ramipril, famotidine, nizatidine, sucralfate, etintidine, tetratolol, minoxidil, chlordiazepoxide, diazepam, amitriptyline, and imipramine.
Preferably, the beneficial agent is a protein or peptide, more preferably a heterologous glycoprotein. Examples of heterologous glycoproteins include molecules such as cytokines and their receptors, as well as chimeric proteins comprising cytokines or their receptors, including, for example tumor necrosis factor alpha and beta, their receptors (TNFR-1; Gray et al., (1990) Proc. Natl. Acad. Sci. USA 87:7380-7384; and TNFR-2; Kohno et al., (1990) Proc. Natl. Acad. Sci. USA 87:8331-8335) and their derivatives; renin; growth hormones, including human growth hormone, bovine growth hormone, methione-human growth hormone, des-phenylalanine human growth hormone, and porcine growth hormone; growth hormone releasing factor (GRF); parathyroid and pituitary hormones; thyroid stimulating hormone; human pancreas hormone releasing factor; lipoproteins; colchicine; prolactin; corticotrophin; thyrotropic hormone; oxytocin; vasopressin; somatostatin; lypressin; pancreozymin; leuprolide; alpha-1-antitrypsin; insulin A-chain; insulin B-chain; proinsulin; follicle stimulating hormone; calcitonin; luteinizing hormone; luteinizing hormone releasing hormone (LHRH); LHRH agonists and antagonists; glucagon; clotting factors such as factor VIIIC, factor IX, tissue factor, and von Willebrands factor; anti-clotting factors such as Protein C; atrial natriuretic factor; lung surfactant; a plasminogen activator other than a tissue-type plasminogen activator (t-PA), for example a urokinase; bombesin; thrombin; hemopoietic growth factor; enkephalinase; RANTES (regulated on activation normally T-cell expressed and secreted); human macrophage inflammatory protein (MIP-1-alpha); a serum albumin such as human serum albumin; mullerian-inhibiting substance; relaxin A-chain; relaxin B-chain; prorelaxin; mouse gonadotropin-associated peptide; chorionic gonadotropin; gonadotropin releasing hormone; bovine somatotropin; porcine somatotropin; a microbial protein, such as beta-lactamase; DNase; inhibin; activin; vascular endothelial growth factor (VEGF); receptors for hormones or growth factors; integrin; protein A or D; rheumatoid factors; a neurotrophic factor such as bone-derived neurotrophic factor (BDNF), neurotrophin-3, -4, -5, or -6 (NT-3, NT-4, NT-5, or NT-6), or a nerve growth factor such as NGF-β; platelet-derived growth factor (PDGF); fibroblast growth factor such as aFGF and bFGF; epidermal growth factor (EGF); transforming growth factor (TGF) such as TGF-alpha and TGF-beta, including TGF-β1, TGF-β2, TGF-β3, TGF-β4, or TGF-β5; insulin-like growth factor-I and -II (IGF-I and IGF-II); des(1-3)-IGF-I (brain IGF-I), insulin-like growth factor binding proteins; CD proteins such as CD-3, CD-4, CD-8, and CD-19; erythropoietin; osteoinductive factors; immunotoxins; a bone morphogenetic protein (BMP); an interferon such as interferon-alpha, -beta, -gamma, and consensus interferon; colony stimulating factors (CSFs), e.g., M-CSF, GM-CSF, and G-CSF; interleukins (ILs), e.g., IL-1 to IL-10; superoxide dismutase; T-cell receptors; surface membrane proteins; decay accelerating factor; viral antigen such as, for example, a portion of the HIV-1 envelope glycoprotein, gp120, gp160 or fragments thereof; transport proteins; homing receptors; addressins; fertility inhibitors such as the prostaglandins; fertility promoters; regulatory proteins; antibodies and chimeric proteins, such as immunoadhesins; analogs and derivatives of these compounds, and pharmaceutically acceptable salts of these compounds, or their analogs or derivatives.
Beneficial agents can also include chemotherapeutic agents, specifically the local application of such agents to avoid or minimize systemic side effects. Compositions containing chemotherapeutic agents may be injected directly into the tumor tissue for sustained delivery of the chemotherapeutic agent over time. In some cases, particularly after resection of the tumor, the composition may be implanted directly into the resulting cavity or may be applied to the remaining tissue as a coating. Representative chemotherapeutic agents that may be delivered include, for example, carboplatin, cisplatin, paclitaxel, BCNU, vincristine, camptothecin, etopside, cytokines, ribozymes, interferons, oligonucleotides and oligonucleotide sequences that inhibit translation or transcription of tumor genes, functional derivatives of the foregoing, and typically known chemotherapeutic agents such as those described in U.S. Pat. No. 5,651,986.
Further examples of beneficial agents include antibacterial agents such as iodine, sulfonamides, mercurials, bisbiguanides, or phenolics; antibiotics such as tetracycline, neomycin, kanamycin, metronidazole, or clindamycin; anti-inflammatory agents such as aspirin, naproxen, ibuprofen, flurbiprofen, indomethacin, eugenol, or hydrocortisone; immune-suppressive or stimulatory agents such as methotrexate or levamasole; immune reagents such as immunoglobulin or antigens; anesthetic agents such as lidocaine or benzocaine; nutritional agents such as amino acids, essential fats, and vitamin C; and antioxidants such as alphatocopherol and butylated hydroxy toluene. The composition may also contain pharmaceutically acceptable carriers and additional ingredients, and these substances may be dissolved or may be suspended.
The beneficial agent, polymer, and solvent components may be mixed together in one step or may be mixed together in separate steps, in any order. It is preferred to dissolve the polymer in the mixed solvent, followed by dissolution of the beneficial agent. Some or all of the mixed solvent or a solvent component may be added to the polymer and/or the beneficial agent in order to solubilize the powder before the composition is mixed together. The various mixing steps can involve heating and/or mechanical mixing in order to form the homogeneous solution.
The amount of beneficial agent in the mixture is preferably equal to a unit dosage. A unit dosage is the amount of beneficial agent necessary to produce the desired beneficial effect in the organism to which it is administered. The absolute amount of a unit dosage can depend on many factors including, for example, the type of agent, the efficacy of the agent, the health of the organism, and the size of the organism.
The concentration of the beneficial agent can be varied, for example according to the amount of dosage required, the release rate, or the solubility of the beneficial agent. The concentration can be from 0.1 milligram per milliliter of solution (mg/ml) to 500 mg/ml, preferably from 5 mg/ml to 250 mg/ml, more preferably from 10 mg/ml to 100 mg/ml. It is preferred that the concentration of the beneficial agent is not so great that a portion of the beneficial agent separates into a separate phase from the solution.
Compositions as described may be administered in a variety of ways. Preferred methods of administration involve injection. Injection may be subcutaneous, parenteral, intramuscular, or other types of injection known to those skilled in the art. A consideration for administration by injection is the viscosity of the mixture. For example, the viscosity of the liquid is preferably sufficiently low to allow the mixture to be injected through a 20 gauge needle. Preferably the solution can be injected through a 25 gauge needle, more preferably through a 28 gauge needle, even more preferably through a 30 gauge needle, even more preferably through a 35 gauge needle. The term "needle" includes all hollow structures used for administration of a beneficial agent, including canulas and catheters. A composition can be injected through a needle when a pressure of 20 psig results in a flow of the composition of at least 1.0 milliliters/minute from the needle.
The viscosity of the liquid can be measured using a CANON-FENSKE viscometer at a temperature of 25� C. (as per ASTM D445-97). The kinematic viscosity of the liquid is preferably at most 2000 centipoise, including 2000-50 centipoise. Examples include less than 1600 centipoise, less than 1400 centipoise, less than 1200 centipoise, less than 1000 centipoise, less than 900 centipoise, less than 800 centipoise, less than 700 centipoise, less than 600 centipoise, less than 500 centipoise, less than 400 centipoise, less than 300 centipoise, less than 200 centipoise, less than 100 centipoise, and less than 50 centipoise, and all ranges therebetween.
For an implant administered by injection, the liquid mixture preferably transforms into a depot upon contact with the fluid in the body. This depot is characterized by its phase separation from the physiological fluid and its increased viscosity relative to the original liquid composition. It is this depot that serves as the polymeric implant for controlled release of the beneficial agent.
One possible mechanism for the release behavior of these compositions involves the phase separation of the beneficial agent within the implant upon administration. As the hydrophilic solvent diffuses into the aqueous surroundings, at least a portion of the beneficial agent separates into a separate phase from the rest of the depot composition. This phase separation then results in a fine suspension of the beneficial agent within the depot. Release of the beneficial agent would then occur slowly and gradually, without an initial burst release or lag time.
When the composition is administered in vivo, preferably less than 25% of the total amount of beneficial agent is released from the depot in 24 hours, more preferably less than 10% of the total amount of beneficial agent is released from the depot in 24 hours, even more preferably less than 5% of the total amount of beneficial agent is released from the depot in 24 hours, even more preferably less than 0.25% of the total amount of beneficial agent is released from the depot in 24 hours, even more preferably less than 0.05% of the total amount of beneficial agent is released from the depot in 24 hours. The organism to which the composition is administered can be, for example, a rat or a human.
The release of the beneficial agent preferably occurs over a period of days, weeks, or months. It is preferred that at least 25% of the total amount of beneficial agent is released within one year of administration, more preferably at least 25% of the total amount of the beneficial agent is released within one month of administration, most preferably at least 25% of the total amount of the beneficial agent is released within one week of administration. Alternatively, it is preferred that at least 20% of the total amount of beneficial agent is released within one year of administration, more preferably at least 20% of the total amount of the beneficial agent is released within one month of administration, most preferably at least 20% of the total amount of the beneficial agent is released within one week of administration. The desired length of the release period will vary according to the physiological treatment desired.
The composition may be conveniently packaged in a sterile container, such as the vial 10 illustrated in
Alternatively, the composition may be packaged in more than one container. For example, a solution of polymer in a solvent or solvent mixture may be in one vial, and a solution of the beneficial agent in a solvent or solvent mixture may be in another vial. The solvents and/or solvent mixture may be the same or different. The contents of the vials may be combined and mixed, and the final composition administered by injection. In another example, the beneficial agent and polymer may be in one container, and the solvent mixture may be in another container. The beneficial agent and polymer may be provided together as a powder, or the beneficial agent and polymer may be provided together as a tablet or capsule. The beneficial agent and polymer may be combined with the solvent mixture such that the polymer and beneficial agent dissolve, and the final composition administered by injection. In another example, the polymer may be provided as a solution in the solvent mixture in a vial, and the beneficial agent may be provided in a separate container. Alternatively, the beneficial agent may be provided as a solution in the solvent mixture in a vial, and the polymer may be provided in a separate container. The contents of the containers may be combined such that a liquid formulation is formed, and the final composition administered by injection.
Preferably, the packaging of the composition or its components is disposable, more preferably recyclable. It is preferred that the composition and its packaging are sterile.
In these examples, compositions containing protein were prepared such that they could be easily administered by injection, yet would provide for a gradual, controlled release of the protein. Release behaviors (release profile) of rhGH (GENENTECH, S. San Francisco, Calif.) from the compositions were studied both in vivo and in vitro by measuring the amount of protein released as a function of time. The stability of the protein was determined by measuring the percentage of the released protein which had not aggregated. A higher percentage of non-aggregated protein indicated better stability.
Poly(L-lactic acid) (PLA) was obtained from BOEHRINGER INGELHEIM, Ridgefield, Conn., as RESOMER 202H, with a reported molecular weight of 12,000 daltons. Polymer solutions were prepared by mixing the benzyl alcohol and benzyl benzoate to form a homogenous mixture. PLA was then added to this mixture and was dissolved by gentle mixing with a vortex mixer. The rhGH was complexed with zinc (10 moles Zn/mole protein), and powders of the complexed protein, sucrose, and surfactant were prepared using a bench top spray dryer.
The relative amounts of ingredients used for making the protein powders and the polymer solutions are given in Tables 1 and 2 respectively. For Examples 1-4, the appropriate protein powder was dissolved in the polymer solution to give an overall concentration of 50 mg/ml of protein. For Example 5, the appropriate protein powder was dissolved in the polymer solution to give an overall concentration of 100 mg/ml of protein. Dissolution was accomplished by gentle mixing with a vortex mixer followed by homogenization at 8000 rpm for 2 minutes, using a 5-mm fine screen shear homogenizer to ensure a uniform solution. The resulting solutions could be injected through a 25-gauge needle.
Concentrations (mg/mL)
Protein Content
Tween 20
(wt %)
Polymer Solution (wt %)
% Non-
in 24 hr
*Added to polymer solution at a concentration of 50 mg/mL
**Determined by SEC-HPLC
***Added to polymer solution at a concentration of 100 mg/mL
For in vitro release studies, 100 microliter (μL) samples of the resulting liquid were placed in 1.5 mL of release buffer and held at 37� C. for 24 hours. The release buffer was 50 mM HEPES, 5 mM EDTA, 0.1 mM NaN3, with a pH of 8.0. The entire release medium was then analyzed by size exclusion chromatography—high performance liquid chromatography (SEC-HPLC) to determine total protein content and percentage of non-aggregated protein present, using a method similar to that described in Maa et. al., J. Pharm Sci. 2(87) 152-159, 1998. The SEC-HPLC was run using a 7.8�300 mm TSK 2000-SWXL column at room temperature, with a mobile phase of 50 mM NaH2PO4, 150 mM NaCl, pH 7.2. The flow rate was 1.0 ml/min, and the run time was 20 min. Protein (10 μg) was injected and the eluent monitored for absorbance at 214 nm. The results of in vitro release after 24 hours are given in Table 2.
Release profiles of the protein from the compositions in vivo were examined by pharmacokinetic studies. In these studies, SD rats were injected with a liquid composition at 5 milligrams protein/kilogram body weight (mg/kg) and 15 mg/kg. Injections were through 25-gauge needles. Serum samples were collected at the time of injection (time=0 hr) and then at the time intervals of 2, 4, 6, 8, 24, 96, and 168 hours. The serum samples were analyzed for rhGH by a specific rhGH ELISA (GENENTECH ASSAY SERVICES), having an assay detection limit of 0.1 nanograms per milliliter (ng/mL), to determine the concentration of rhGH in each sample. This protein concentration is due to the release of the protein from the implant. The resulting graphs of protein release over time are illustrated in
A comparative graph of Examples 1 and 5 is illustrated in
rhGH Levels in Serum
Average 0-2
Average 0-7
(ng* day/mL)
(ng* day/mL)
A (50 mg/mL)
B (100 mg/mL)
In this example, an injectable composition for controlled release of a protein was prepared. Release profiles of the protein from the composition were studied both in vivo and in vitro by measuring the amount of protein released as a function of time.
An aqueous protein solution was prepared by mixing VEGF (10 mg/ml), sucrose (10 mg/ml), 0.03% POLYSORBATE 80, and histidine (10 mM). The solution had a pH of 6.0. This protein solution was sprayed into liquid nitrogen using an ultrasonic nebulizer, as described in U.S. Pat. No. 5,019,400. The resulting frozen protein droplets were then lyophilized to produce particles having a diameter of 2-10 μm. The protein powder was mixed into a polymer solution composed of 30 wt % PLA, 69 wt % benzyl benzoate, and 1 wt % benzyl alcohol. The mixture was made by homogenization at 8,000 rpm for 2 minutes. The resulting mixture contained 12 mg protein per milliliter of liquid.
For in vitro release studies, 100 microliter (μl) samples were injected into 1.5 ml of a release buffer and held at 37� C. The release buffer was an aqueous mixture having a pH of 7.0, containing 10 mM histidine, 140 mM NaCl, 0.02% POLYSORBATE 20, and 0.02% sodium azide. At given intervals of time, the entire release medium was replaced with fresh buffer, the medium was then analyzed by SEC-HPLC to determine total protein content. The SEC-HPLC was run using a 7.8�300 mm TSK 300-SW column, having 5 μm particles, at room temperature. The mobile phase was 25 mM NaH2PO4, 1.0 M NaCl with a of pH 7.4. The flow rate was 1.0 mL/min, and the run time was 20 min. Protein (25 μg) was injected and the eluent monitored for absorbance at 214 nm.
After 24 hours at 37� C., approximately 0.2% of the VEGF had been released. After an additional 168 hours, approximately 0.1% more of the VEGF was released.
The release profile of the protein from the composition in vivo was examined by pharmacokinetic studies. In this study, SD rats weighing between 265 g and 302 g were injected with a liquid composition at 3.6 mg/kg (dose volume of 0.3 ml/kg). Injections were through 25-gauge needles. Whole blood was collected from the rats in EDTA-treated microtainers and plasma harvested. The plasma samples were frozen until analysis and were then assayed using a VEGF ELISA to determine the concentration of VEGF in each sample. This protein concentration is due to the release of the protein from the implant. The resulting graph of protein release over time is illustrated in
Obviously, numerous modifications and variations of the present invention are possible in light of the above teachings. It is therefore to be understood that within the scope of the appended claims, the invention may be practiced otherwise than as specifically described herein.
|Cited Patent
|Filing date
|Publication date
|Apr 23, 1980
|Oct 27, 1981
|Behringwerke Aktiengesellschaft
|Blood coagulation factors and process for their manufacture
|Oct 3, 1988
|Jul 3, 1990
|Dunn Richard L
|Biodegradable in-situ forming implants and methods of producing the same
|Dec 19, 1988
|Dec 4, 1990
|Vipont Pharmaceutical, Inc.
|Muscosal delivery systems for treatment of periodontal disease
|May 1, 1989
|May 28, 1991
|Enzytech, Inc.
|Very low temperature casting of controlled release microspheres
|Jul 24, 1989
|Dec 31, 1991
|Vipont Pharmaceutical, Inc.
|Biodegradable system for regenerating the periodontium
|Apr 15, 1988
|Mar 17, 1992
|Genentech, Inc.
|Human growth hormone formulation
|Nov 17, 1989
|Jul 28, 1992
|Atrix Laboratories, Inc.
|Purification of benzophenanthridine alkaloids extracts from alkaloid extracts
|Oct 13, 1992
|Sep 7, 1993
|The Procter & Gamble Company
|Sustained release compositions for treating periodontal disease
|Apr 24, 1990
|Jan 11, 1994
|Atrix Laboratories, Inc.
|Biodegradable in-situ forming implants and methods of producing the same
|Dec 23, 1991
|Jan 11, 1994
|Atrix Laboratories, Inc.
|Biodegradable in-situ forming implants and methods of producing the same
|Oct 28, 1991
|Jun 28, 1994
|Atrix Laboratories, Inc.
|Biodegradable polymer composition
|Apr 13, 1993
|Jun 28, 1994
|Vipont Pharmaceutical, Inc.
|Intragingival delivery systems for treatment of periodontal disease
|Dec 23, 1991
|Aug 23, 1994
|Atrix Laboratories, Inc.
|Biodegradable in-situ forming implants and methods for producing the same
|Jun 29, 1993
|Nov 29, 1994
|Atrix Laboratories, Inc.
|Biodegradable system for regenerating the periodontium
|Sep 28, 1993
|Jan 30, 1996
|Atrix Laboratories, Inc.
|Biodegradable implant precursor
|Mar 30, 1994
|Sep 17, 1996
|Reilly Industries, Inc.
|Physically-modified degradable thermoplastic compositions
|Feb 17, 1994
|Dec 31, 1996
|Genentech, Inc.
|Excipient stabilization of polypeptides treated with organic solvents
|Jan 24, 1995
|Jan 7, 1997
|Takeda Chemical Industries, Ltd.
|Water-soluble composition for sustained-release
|May 26, 1994
|Feb 4, 1997
|Atrix Laboratories, Inc.
|Biodegradable polymer composition
|Jun 14, 1996
|Jul 29, 1997
|Massachusetts Institute Of Technology
|Controlled local delivery of chemotherapeutic agents for treating solid tumors
|Sep 30, 1996
|Sep 9, 1997
|Takeda Chemical Industries, Ltd.
|Matrix for sustained-release preparation
|Jun 7, 1995
|May 5, 1998
|Southern Biosystems, Inc.
|High viscosity liquid controlled delivery system
|Dec 5, 1996
|Jul 14, 1998
|Atrix Laboratories, Inc.
|Liquid delivery compositions
|Apr 10, 1997
|Jul 21, 1998
|Alza Corporation
|Injectable drug delivery system and method
|Apr 7, 1998
|Jun 15, 1999
|Alkermes Controlled Therapeutics, Inc.
|Modulated release from biocompatible polymers
|Aug 8, 1997
|Aug 31, 1999
|Atrix Laboratories, Inc.
|Polymeric compositions useful as controlled release implants
|Jan 28, 1999
|Oct 26, 1999
|Alza Corporation
|Peptide/protein suspending formulations
|Jan 16, 1996
|Nov 9, 1999
|Societe De Conseils De Recherches Et D'applications Scientifique S.A.
|Sustained release drug formulations
|Jul 22, 1994
|Dec 28, 1999
|Massachusetts Institute Of Technology
|Nanoparticles and microparticles of non-linear hydrophilic-hydrophobic multiblock copolymers
|Dec 9, 1997
|Mar 21, 2000
|Alza Corporation
|Pharmaceutical hydrogel formulations, and associated drug delivery devices and methods
|Feb 19, 1999
|Apr 18, 2000
|Alkermes Controlled Therapeutics, Inc.
|Composition for sustained release of human growth hormone
|Apr 16, 1999
|May 23, 2000
|Alza Corporation
|Non-aqueous protic peptide formulations
|Nov 7, 1997
|Jun 27, 2000
|Genentech, Inc.
|Method for drying microspheres
|Apr 22, 1996
|Jul 11, 2000
|Takeda Chemical Industries, Ltd.
|Sustained-release preparation
|Mar 5, 1999
|Aug 29, 2000
|Alkermes Controlled Therapeutics Inc.
|Preparation of biodegradable, biocompatible microparticles containing a biologically active agent
|Oct 31, 1997
|Sep 5, 2000
|Takeda Chemical Industries, Ltd.
|Sustained-release preparation capable of releasing a physiologically active substance
|Jun 13, 1997
|Sep 5, 2000
|Genentech, Inc.
|Controlled release microencapsulated NGF formulation
|Mar 30, 1999
|Sep 19, 2000
|Atrix Laboratories, Inc.
|Non-polymeric sustained release delivery system
|Apr 19, 1999
|Sep 26, 2000
|Alza Corporation
|Non-aqueous polar aprotic peptide formulations
|Dec 18, 1997
|Oct 10, 2000
|Alza Corporation
|Gel composition and methods
|Oct 28, 1998
|Nov 7, 2000
|Atrix Laboratories, Inc.
|Controlled release liquid delivery compositions with low initial drug burst
|Mar 24, 1993
|Nov 14, 2000
|Alza Corporation
|System for delaying drug delivery up to seven hours
|Mar 7, 1997
|Dec 26, 2000
|Alkermes Controlled Therapeutics, Inc.
|Controlled release of metal cation-stabilized interferon
|Jul 14, 1999
|Jan 16, 2001
|Alza Corporation
|Dosage form comprising liquid formulation
|Dec 13, 1996
|Feb 20, 2001
|Takeda Chemical Industries, Ltd.
|Production of sustained-release preparation for injection
|Sep 11, 1998
|Feb 20, 2001
|Takeda Chemical Industries, Ltd.
|Complex of human growth hormone and zinc
|Dec 18, 1997
|Mar 6, 2001
|Takeda Chemical Industries, Ltd.
|Method of producing a sustained-release preparation
|Dec 18, 1997
|Dec 18, 2001
|Alza Corporation
|Injectable depot gel composition and method of preparing the composition
|Apr 22, 1994
|Apr 16, 2002
|Insite Vision Incorporated
|Plasticized bioerodible controlled delivery system
|Jul 13, 2000
|Oct 22, 2002
|Alza Corporation
|Gel composition and methods
|Nov 25, 2001
|Mar 21, 2002
|Brodbeck Kevin J.
|Injectable depot gel composition and method of preparing the composition
|Aug 19, 2002
|Mar 6, 2003
|Brodbeck Kevin J.
|Gel composition and methods
|Mar 18, 1999
|Sep 23, 1999
|Merck & Co., Inc.
|Liquid polymeric compositions for controlled release of bioactive substances
|Aug 12, 1986
|Apr 1, 1987
|International Minerals And Chemical Corporation
|Prolonged release of growth promoting hormones
|Jul 19, 1991
|Jan 22, 1992
|University Of Kentucky Research Foundation
|Drug delivery system involving interaction between protein or polypeptide and hydrophobic biodegradable polymer
|Jun 20, 1990
|Jan 19, 1994
|Atrix Laboratories, Inc.
|Biodegradable system for regenerating the periodontium
|Dec 18, 1997
|Jul 18, 2001
|Alza Corporation
|Injectable depot gel composition and method of preparing the composition
|Title not available
|Title not available
|Title not available
|Title not available
|Oct 27, 1988
|May 5, 1989
|Dainippon Pharmaceutical Co., Ltd.
|Sustained-release preparation
|Mar 25, 1992
|Oct 15, 1992
|Genentech, Inc.
|Stable growth hormone metal ion formulations
|Jan 15, 1997
|Jul 24, 1997
|Sustained release drug formulations
|Dec 18, 1997
|Jul 2, 1998
|Alza Corporation
|Injectable depot gel composition and method of preparing the composition
|Dec 18, 1997
|Jul 2, 1998
|Alza Corporation
|Gel composition and methods
|Mar 18, 1999
|Sep 23, 1999
|Merck & Co., Inc.
|Liquid polymeric compositions for controlled release of bioactive substances
|May 18, 2000
|Dec 28, 2000
|Southern Biosystems, Inc.
|COMPOSITIONS FOR CONTROLLED RELEASE OF THE HORMONE GnRH AND ITS ANALOGS
|Feb 26, 2001
|Jan 3, 2002
|Shukla Atul J
|Biodegradable vehicles and delivery systems of biologically active substances
|Nov 14, 2002
|May 22, 2003
|Alza Corporation
|Injectable depot compositions and uses thereof
|Nov 14, 2002
|May 22, 2003
|Alza Corporation
|Catheter injectable depot compositions and uses thereof
|Arakawa et al., "Protein-Solvent Interactions in Pharmaceutical Formulations", Pharmaceutical Research, vol. 8, No. 3 (1991) 285-291.
|Gray et al., "Cloning of human tumor necrosis factor (TNF) receptor cDNA and expression of recombinant soluble TNF-binding protein", Proc. Natl. Acad. Sci. USA, vol. 87 (1990) 7380-7384.
|Hawley's Medical Dictionary, "Emulsion", 14th Edition, 2002.
|Israeli Office Action for Application No. 157531, dated Jul. 25, 2007, 2 pages (English Translation only).
|Johnson et al., "A month-long effect from a single injection of microencapsulated human growth hormone", Nature Medicine, vol. 2, No. 7 (1996) 795-799.
|Kita et al., "Contribution of the Surface Free Energy Perturbation to Protein-Solvent Interactions", Biochemistry, vol. 33 (1994) 15178-15189.
|Kohno et al., "A second tumor necrosis factor receptor gene product can shed a naturally occurring tumor necrosis factor inhibitor", Proc. Natl. Acad. Sci. USA, vol. 87 (1990) 8331-8335.
|Lai et al., "Metal and RNA Binding Properties of the hdm2 Ring Finger Domain", Biochemistry, vol. 37, No. 48 (1998) 17005-17015.
|Lfe Science Dictionary, "Emulsion", 1995-1998.
|Lin et al., "On the role of surface tension in the stabilization of globular proteins", Protein Science, vol. 5 (1996) 372-381.
|Maa et al., "Spray-Drying of Air-Liquid Interface Sensitive Recombinant Human Growth Hormone", Journal of Pharmaceutical Sciences, vol. 87, No. 2 (1998) 152-159.
|Sackett et al., "Multivalent Cations Depress Ligand Binding to Cell-Associated Insulin-Like Growth Factor Binding Protein-5 on Human Glioblastoma Cells", Endocrinology, vol. 139, No. 4 (1998) 1943-1951.
|Smith et al., "A Novel Parenteral Delivery System", Pharmaceutical Research, PDD 7270, vol. 13, No. 3 (1996) 1 page.
|Timasheff, S.N., "Control of Protein Stability and Reactions by Weakly Interacting Cosolvents: The Simplicity of the Complicated", Advances in Protein Chemistry, vol. 51 (1998) 355-432.
|Timasheff, S.N., "Solvent Stabilization of Protein Structure", Methods in Molecular Biology, vol. 40 (1995) 253-269.
|Timasheff, S.N., "The Control of Protein Stability and Association by Weak Interactions with Water: How Do Solvents Affect These Processes?" Annu. Rev. Biophys. Biomol. Struct., vol. 22 (1993) 67-97.
|Xie et al., "The thermodynamic mechanism of protein stabilization by trehalose", Biophysical Chemistry, vol. 64 (1997) 25-43.
|Yang et al., "Effect of Zinc Binding and Precipitation on Structures of Recombinant Human Growth Hormone and Nerve Growth Factor", Journal of Pharmaceutical Sciences, vol. 89, No. 11 (2000) 1480-1485.
|Citing Patent
|Filing date
|Publication date
|Jun 24, 2010
|Aug 6, 2013
|Genentech, Inc.
|Bioerodible polymers for injection
|Jan 14, 2016
|Feb 21, 2017
|Durect Corporation
|Compositions and methods involving polymer, solvent, and high viscosity liquid carrier material
|Mar 11, 2014
|Aug 22, 2017
|Durect Corporation
|Injectable controlled release composition comprising high viscosity liquid carrier
|Jun 24, 2010
|Jun 23, 2011
|Cleland Jeffrey L
|Erodible polymers for injection
|U.S. Classification
|International Classification
|Cooperative Classification
|European Classification
|May 23, 2002
Owner name: GENENTECH, INC., CALIFORNIA
Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:CLELAND, JEFFREY;OKUMU, FRANKLIN;REEL/FRAME:012924/0053;SIGNING DATES FROM 20020513 TO 20020517
Owner name: GENENTECH, INC., CALIFORNIA
Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:CLELAND, JEFFREY;OKUMU, FRANKLIN;SIGNING DATES FROM 20020513 TO 20020517;REEL/FRAME:012924/0053
|Apr 24, 2014
|Fee payment
Year of fee payment: 4


text:
June 2, 2005
Jan Edling, a little-known labor-union economist from the big LO blue-collar union, is suddenly in the policy spotlight with his assertion that Sweden's real jobless rate is really closer to 20 percent than the official 5.5 percent rate.
He suspects that the government is putting people into other benefit categories that other countries would simply put into the unemployment column:
- Beyond the official rate, an additional 4.4 percent of the working-age population are parked in the government's elaborate array of job-creation and training programs, according to a study by Skandinaviska Enskilda Banken AB with data from Statistics Sweden.
- But Edling calculates that another 10 percent of working-age people can be identified as unemployed, using correlations between unemployment, long-term sickness and early retirement among Sweden's municipalities and regions.
- This makes the actual unemployment rate closer to 20 percent of the work force, he says.
Instead of urging the overhaul of the labor market and welfare and tax regime, Edling says his aim was to show that regions investing heavily in infrastructure, research and education for job mobility did better than regions that didn't. Typically, he explains, the latter had more hidden unemployment.
"The public debate is about statistics, but they are only a symptom of something that is wrong in this country," says Edling. "What we see are people at Electrolux who lose their jobs and don't know anything else than how to make vacuum cleaners. Chances are they will soon be in early retirement."
Source: Terence Roth, "Sweden's Hidden Jobless: Labor Economist Asserts Unemployment Near 20%," Wall Street Journal, June 1, 2005.
For text (subscription required):
Browse more articles on International Issues


text: Honda City is premium sedan that comes with great performance and unparalleled driving comfort from the house of Honda Motors. Now you can avail Honda City exclusively for your rental needs with our amazing rental packages. This car is available for all kinds of private hire for small groups of four people or less for airport transfers, city traveling, sightseeing, local transfers and outstation trips. Contact us to find the best rental deal now!


text:
Post From Dinar Updates
Chat Room Excerpts & Highlights
Dinar Updates Sunday AM Chat 4-10-16 Part 3 of 3
rcookie says to Hutch():GONNA PUT UP SOME INFO ABOUT AUCTIONS....SO WHEN SOME OF THE COMMENTS THAT HOLLY'S BANKERS BRING IN HAVE SOME PERSPECTIVE AND CLARITY...
rcookie says():the Central Bank of Iraq regulates the flow of money through controlled auctions
rcookie says():this is not normal. In most other countries, money can be easily exchanged into a number of currencies at the will and whim of any citizen. The exchange rates are allowed to move freely according to the forces of supply and demand, interest rates, etc.
Soonergirlie says():ok, i see now
rcookie says():"Every day since 2004, the CBI has held an auction through which hard currency is sold to banks, companies and traders in exchange for evidence of import and transaction receipts. The auctions aim to prevent market speculation and stabilize the exchange rate of Iraqi dinars to the US dollar
rcookie says():The purpose of these auctions is to control the IQD:USD exchange rate by controlling the amount of USD circulating in Iraq. At these auctions, USD is issued exclusively to banks, companies and traders for the purpose of conducting business transactions with foreign entities (ie: importers, securities traders, banks, etc).
rcookie says():By controlling the amount of USD available in Iraq, the Iraqi government controls the value of the USD relative to its own currency, thereby stabilizing the dinar. It is as close as you can get to an outright currency peg.
rcookie says():Cracking Down on Auction Abuses
Things were going really great for years, until evidence turned up that some buyers at these auctions were falsifying their transaction receipts, enabling them to purchase more USD than their business activity legitimately entitled them to have.
Hutch says to rcookie():trying to keep it clean while allowing them to conduct business
rcookie says():The government believes much of the excess dollars purchased were smuggled across the border into Iran, which has a shortage of hard international currency due to sanctions. Money laundering and black market demand account for the remainder of auction abuses.
rcookie says():The supply/demand ratio dictates that the more supply you have of something, the cheaper its value. More USD in circulation than previously thought meant a cheaper USD, which meant a stronger dinar.
rcookie says():"The CBI prohibited any bank or company with capital of less than $400,000 from taking part in the currency auction. Additionally, all participants had to submit their [transaction receipts] to the criminal division in the Ministry of Interior, the economic crime unit and the money-laundering division of the CBI for approval."
rcookie says():Reducing the number of buyers at the auctions meant reducing the amount of USD making it into circulation, strengthening the USD relative to the Iraqi dinar, and weakening the dinar back to that desired target level.
rcookie says():Anger Over Weakening Dinar
Iraqi citizens and businesses who do not have dealings with foreign entities are understandably angered by CBI controls aimed at keeping the dinar weak. A weak currency means citizens and businesses need to pay more for goods and services, especially since so many goods are still being imported from abroad.
rcookie says():Amin Abbas stressed to Al-Monitor that the CBI must take "full responsibility for the fall of the … Iraqi dinar … because of its restrictive measures in granting permits to exchange companies." And Mohammed Khalil, an official on Iraq's Economic and Investment Committee, accused the CBI of deliberately "hinder[ing] the flow of US dollars into the market."
rcookie says():Others are pinning the blame on Iraqi banks, as Al-Monitor informs:
"Hussein al-Yasiri said some banks have stopped selling dollars to regular customers and instead have been selling them to exchange companies. This has prompted Iraqis to buy dollars from the exchange companies at prices favorable to the companies. The exchanges are not subject to government monitoring
rcookie says():NO CONTROL OVER THE VIGS!!!!!!!!!
rcookie says():And Iranian involvement is still suspected by Ahmed al-Alwani, head of the Iraqi parliament's economic committee, who believes Iran is supplying Iraqi partners with false trade receipts in order to obtain USD from the auctions.
Hutch says to rcookie():still trying to beat the system
rcookie says():But Ahmed Bureihi, a former senior official at the CBI, denied such accusations. "Iran has nothing to do with the increased exchange rate," he told Al-Monitor. "The CBI sells foreign currency to Iraqi customers to be used in funding trade transactions outside the country." "There are Iraqi traders who defraud the CBI and provide counterfeit documents of virtual imports to Iraq. However … this has nothing to do with political issues."
rcookie says():THAT IS CALLED THE PINOCCHIO EFFECT.......LOL
rcookie says():HIGHLY TECHNICAL ECONOMIC TERM.....LOL
puffdragon says to rcookie():I dont understand Rcookie ({)(@)
rcookie says():On the dinar's side of that equation, as more oil is exported, more revenue is generated, and the nation becomes wealthier "per capita". Enabled by this increased wealth, the government starts funding sorely needed rebuilding and expansion projects on infrastructure, energy, education, health care, and industry. In so doing, it pumps more of its local currency into circulation, which in turn weakens it.
This is a valid explanation for the stronger USD and weaker IQD. However, what the CBI is reluctant to admit is that apart from these increased oil revenues, the government is controlling the dinar's exchange rate by controlling the amount of USD in circulation via its daily auctions.
Dr Dave says():A year ago their auctions were often over 200 million with 10-12 banks not the 30 banks like today
rcookie says():THAT IS EXACTLY WHAT THEY ARE SAYING...
Dr Dave says():slow on the up take
rcookie says():AND WHERE IS THAT CURRENCY...
rcookie says():HOW DID IT GET OUTSIDE IRAQS BORDERS...
Dr Dave says():Shell co's?
Dr Dave says():Ask Allawi he may know
rcookie says():THEIR LEGITIMATE TRADE NUMBERS DO NOT JIVE WITH OIL SALES OR THE CURRENCY LIQUIDITY CRISIS IN THE MARKETPLACE....
rcookie says():THIS IS WHY THE CURRENT TIGHTENING INSTRUMENTS AND ACTIONS ARE ONGOING.....
Dr Dave says():Tightening instruments.......Tuner???.......Sadr will do this
rcookie says():CITIZENS CAN NOW PURCHASE CURRENCY IN RAFIDAIN AUCTION WINDOWS DIRECTLY...AT A CBI CONTROLLED AND CAPPED RATE AND DIFFUSE THE STRENGTH AND OPTION OF PARALLEL MARKETS WITH INFLATED RATES...
rcookie says():THIS IS EXTREMELY IMPORTANT RELATIVE TO THE 2% SPREAD...INTEGRAL TO ARTICLE VIII OBLIGATIONS.....
Baxter says():Rcookie... are they within the 2% spread now?
rcookie says():TIGHTENI NG INSTRUMENTS....75% VOLUME REDUCTION...WINDOWS TO CITIZENS FOR DIRECT PURCHASE AT NEWLY OPENED 1 STOP SHOP RAFIDAIN BANKS....
Dr Dave says():3000 dinar......for medical tx......a bandaide?
Dr Dave says():that is tight
Baxter says(2):what is that.. about 25 USD?
Dr Dave says():3.00
Baxter says():OH WOW>.
Baxter says():3 Bucks...
Baxter says():they can leave the country ... with 3 dollars?
Dr Dave says():get a million for a thousand
Dr Dave says():ish
rcookie says():STABILIZED ARRANGEMENT....
Classification as a stabilized arrangement entails a spot market exchange rate that remains within a margin of 2% for six months or more (with the exception of a specified number of outliers or step adjustments) and is not floating.
rcookie says():WITH EXCEPTION OF SPECIFIED NUMBER OF OUTLIERS OR STEP ADJUSTMENTS....
niterider says():Does anyone no if theirs going to be a call today at 4 eastern time ???
Dr Dave says():not 90 days like Kap suggests
Baxter says():well.. thats worse isnt it?
rcookie says():NOT A ALL OR NOTHING STIPULATION....
Dr Dave says():no
Dr Dave says():keep it within that spread
niterider says():thank you!!
Baxter says():Kap had a post last week that they were over 6% in the spread... whether thats true or not... I dont have a clue... I dont know how to figure it...
jeffusa says():(IraqiNews.com) al-Anbar – A security source in Anbar province said on Saturday, that the international coalition destructed a rockets launcher belonging to the ISIS west of the city of Ramadi.
The source said in a statement followed by IraqiNews.com, "The international coalition bombarded a rockets launcher and a machine gun called Hellfire belonging to the ISIS in al-Baghdadi Island north of al-Baghdadi vicinity (90 km west of Ramadi), resulting in the complete destruction of them and all the elements that were in charge of the detachment."
The statement added, "The international coalition also bombed one of the ISIS sites in al-Baghdadi Island, resulting in killing seven ISIS elements, in addition to inflicting material and human losses upon them."
rcookie says():IT IS NOT AN ALL OR NOTHING STIPULATION.....
wmawhite says to Baxter():Either do most people............all last summer people were crying about th eCBI's spread being out of wack.........well, read the IMF Technicla Letter of Intent,.....they said that as of August 2015 that the CBI spread was at 2%.
wmawhite says to Baxter():Technical*
Baxter says():WMA... is it still ? does it have to remain there... or what happens if it was at 2% and now its not...
wmawhite says to Baxter():So,........lets ask the question; regarding the central bank 2% requirement, who knows more about thhe subject,.......the IMF or a guru?
jeffusa says to wmawhite():if your the guru ...i'll take you (y)
jarhead says to jeffusa():SHUP old man
wmawhite says to Baxter():My point is this;........all last summer Kap was stating that the spread was out of wack,.....the IMF says it was not. Question,....who do you think knows more about the spread? Kap or the IMF?
jeffusa says to jarhead():you SHUP old dude
Baxter says():well... theIMF... im sure..
puffdragon says():Saw nightrider ask about a call today is that true and could someone tell me that time please !
wmawhite says to jeffusa():Thank you......but I really don't know anything......although I did stay at a Holiday Inn Express...........lol
jeffusa says to wmawhite():nice
jeffusa says to wmawhite():lol
jeffusa says():ERBIL, Kurdistan Region – More than 11,000 families have returned to areas of Iraq's Anbar province that have been liberated from the Islamic State (ISIS) group, an Iraqi official said.
"During the past days, more than 11,000 families returned to the liberated areas in the province," Ibrahim Awsaij, mayor of Anbar's capital, Ramadi, told reporters on Saturday.
The families will be settled in the neighborhoods of Tamim, al- Qatana, al-Malab and al-Andalws in Ramadi, he said.
"So far, the number has risen to 11,150 families," who have returned, the mayor added.
In December, the Iraqi army said it had defeated ISIS in Ramadi and that it had taken control of government buildings in the city center.
jeffusa says():The mayor said that a special committee has been formed to investigate the identities of returned families, presumably to ensure that there are no ISIS militants hiding among them.
The Iraqi army, backed by US air support, retook a vast majority of Ramadi from ISIS seven months after it fell to the militants. But ISIS still controls pockets of resistance in the westernmost parts of Anbar, namely Qaim.
In Anbar, Iraqi forces also have been advancing in the small Ramadi town of Hit, where they say they have captured several districts and liberate 1,000 families held hostage by ISIS.
http://rudaw.net/eng.../iraq/100420162 bad link
puffdragon says to niterider():TY nightrider
wmawhite says to Baxter():OK..........now, concerning the spread, I would think that they are communicating with the CBI and the CBI is doing exactly what they ought to be doing, based upon last year.
rcookie says():The required margin of stability can be met either with respect to a single currency or a basket of currencies, where the anchor currency or the basket is ascertained or confirmed using statistical techniques.
Classification as a stabilized arrangement requires that the statistical crite- ria are met and that the exchange rate remains stable as a result of official action (including structural market rigidities). The classification does not imply a policy commitment on the part of the country authorities.
Your comment will be posted after it is approved.
Leave a Reply.


text:
Edmond Outdoor Ice Rink
Edmond, OK 73003
Enjoy holiday ice skating in Mitch Park at the Edmond Outdoor Ice Rink. Glide around the 117ft. x 56ft....Learn More
Enjoy holiday ice skating in Mitch Park at the Edmond Outdoor Ice Rink. Glide around the 117ft. x 56ft....Learn More
Lace up your running shoes and visit downtown Edmond on Thanksgiving morning for the Turkey Trot. This 5K run and one...Learn More
Held at the Sapulpa Elks Lodge in Sapulpa OK, the Native American Christmas Market welcomes Native...Learn More
Hear talented violinist Ray Chen at the Armstrong Auditorium in Edmond. Chen is the winner of two of the world's...Learn More
The Boys Ranch Town Drive-Thru Christmas Pageant has been an annual gift from Boys Ranch Town to the community and...Learn More
Bring the entire family out to UCO WinterGlow in Edmond for an evening of holiday festivities. The event kicks off at...Learn More
Don't miss out on Holiday Hop in Edmond, a free family event that lets you create a holiday craft in the Edmond...Learn More
Come and enjoy this holiday-themed parade along Route 66. The annual Stroud Christmas event kicks off at 5:30pm...Learn More
Come enjoy an old-fashioned holiday parade with festive lights at the Sapulpa Christmas Parade, held in historic...Learn More
Local artists fill the Round Barn in Arcadia with the sound of acoustic music once a month. The Round Barn...Learn More
Join experts with the Edmond Historic Preservation Trust to learn something new with a downtown tour of historic Edmond....Learn More
For a lovely Christmas experience, visit the Live Nativity the day before Christmas Eve at Edmond's First United...Learn More
Come out and see migrating bald eagles in all their grace and beauty during the Arcadia Lake Eagle...Learn More
Banjo virtuoso Béla Fleck and the string quartet Brooklyn Rider are teaming up for a memorable evening at the...Learn More
The Moscow Festival Ballet brings a stunning gala to the Armstrong Auditorium in Edmond. The first night's program...Learn More
Head to Mitch Park in Edmond for the Frigid Five Race to get your blood pumping. Take off across the park and...Learn More
Tap your toes to the sights and sounds of Dublin Irish Dance at the Armstrong Auditorium in Edmond. This eight member...Learn More
Founded in 1491, the Staatskapelle Weimar is one of the oldest and most illustrious orchestras in the world. It is...Learn More
Enjoy traditional Native American singing, dancing and drumming at the UCO Spring Powwow. The event kicks off with the...Learn More
The Herbert W. Armstrong College Choral Union is bringing the tale of Abraham from the Old Testament to Edmond. Directed...Learn More
Over 100 artists exhibit and sell their works of art at the Downtown Edmond Arts Festival each year. Come to this event...Learn More
Enjoy a night of big band at the Armstrong Auditorium in Edmond. Formed in 1956, the Glenn Miller Orchestra brings their...Learn More
The University of Central Oklahoma in Edmond is proud to present the annual UCO Endeavor Games for athletes with...Learn More
Spend the afternoon enjoying endless scoops of delicious ice cream at the annual Ice Cream Festival in...Learn More
Stroud has the distinction and honor of being Oklahoma's Winery and Grape Capital and also has the wonderful...Learn More
Come to the historic Route 66 town of Chandler for a car, truck and bike show that's sure to be fun for the whole...Learn More
The Stroud Fire Department invites guests to come on down and admire their shiny red fire trucks at the Mother Road Fire...Learn More
Visit the Edmond Quilt Festival for tons of vendors, demonstrations and door prizes. Guests can browse the 100...Learn More
Head to the Jingle Bell Bazaar in Edmond and start your Christmas shopping early. This show features a wide variety of...Learn More
Lace up your running shoes and visit downtown Edmond on Thanksgiving morning for the Turkey Trot. This 5K run and one...Learn More
The Boys Ranch Town Drive-Thru Christmas Pageant has been an annual gift from Boys Ranch Town to the community and...Learn More


text: I noticed that this is being released in region 2 this week. Is there any word of a possible region 1 release in the near future? Special Features on the region 2 disc: * Over 2 hours of additional material! * Interviews with Terry Gilliam, Johnny Depp, Kieth Fulton and Louis Pepe * Deleted scenes * 2 alternative openings * Video portraits * Costume design and storyboards from 'The Man Who Killed Don Quixote' * Interactive menus * Scene selection. Has anyone purchased this as of yet?


text:
Dark Shadows - The Haunting of Collinwood
Dark Shadows - The Haunting of Collinwood
We're sorry! This product is not available.
Featured Products
Description & Features+
Named one of TV's top 24 Cult Shows by TV GUIDE!
An exorcist is summoned after the children at Collinwood are possessed
High atop Widows' Hill off the stormy Maine coast sits the foreboding Collinwood, home for centuries of the wealthy Collins family.
The Gothic television classic DARK SHADOWS attracted a fiercely devoted following during its airings on ABC-TV from 1966-71. The character of Barnabas Collins, a sympathetic vampire, turned the series into a must-see event for over 20 million viewers.
In this special release, the story of how the ghost of Quentin Collins haunted the eerie estate of Collinwood is detailed in a selection of scenes from the most popular episodes.
The children become possessed when ghosts take over the eerie Collinwood estate
From the Manufacturer +


text: OK so I rooted using Z4Root, it worked great I am all rooted up, but I really want 2.2 does anyone know how I can go about getting it? I have heard that some of the fasinate romes work for the mesmerize ,but I am nervous about those. Any help or info would be greatly appriciated. Thanks