text:
Compact digital still camera w/ built-in flash, 12x Optical Zoom & 4x Digital & 48x Combined Zoom and Optical Image Stabilizer
12.1 Megapixel, 1/2.3-inch CMOS
Total Pixels
Approx. 12.8 Megapixels
Effective Pixels
Approx. 12.1 Megapixels
Focal Length
5.0 (W) - 60.0 (T) mm (35mm film equivalent: 28 (W) - 336 (T) mm)
Digital Zoom
Approx. 4.0x (Up to approx. 48x in combinations with the optical zoom)
Focusing Range
Auto: 0.4 in. (1 cm) - infinity (W), 3.3 ft. (1 m) - infinity (T)
Normal AF: 2.0 in. (5cm) - infinity (W), 3.3 ft. (1m) - infinity (T)
Macro AF: 0.4 in. - 1.6 ft. (1-50cm) (W)
Autofocus System
TTL Autofocus
Optical Viewfinder
LCD Monitor
3.2-inch wide TFT Color Touch Panel LCD with wide viewing angle
LCD Pixels
Approx. 461,000 dots
LCD Coverage
Approx. 100%
Maximum Aperture
f/3.4 (W) - f/5.9 (T)
Shutter Speed
1-1/4000 sec.
15-1/4000 sec. (Total shutter speed range)
Auto, ISO 100/200/400/800/1600/3200 (in P mode)
Light Metering Method
Evaluative, Center weighted average, Spot
Exposure Control Method
AE Lock
Exposure Compensation
+/-2 stops in 1/3-stop increments
White Balance Control
Auto, Daylight, Cloudy, Tungsten, Fluorescent, Fluorescent H, Custom
Built-in Flash
Auto, Flash On, Slow Synchro, Flash Off
Flash Range
12 in. - 10.2 ft. (30 cm-3.1 m) (W), 3.3 - 5.6 ft. (1.0 - 1.7 m) (T)
Recycling Time
10 sec. or less (battery voltage: 3.7 V)
Flash Exposure Compensation
Shooting Modes
Auto*1, P, Movie Digest, Portrait, Kids & Pets, Smart Shutter*2, High-Speed Burst, Best Image Selection, Handheld Night Scene, Low Light, Fish-eye Effect, Miniature Effect, Toy Camera Effect, Monochrome, Super Vivid, Poster Effect, Color Accent, Color Swap, Beach, Foliage, Snow, Fireworks, Long Shutter, iFrame Movie, Super Slow Motion Movie
Photo Effects
My Colors Off, Vivid, Neutral, Sepia, Black & White, Positive Film, Lighter Skin, Darker Skin, Vivid Blue, Vivid Green, Vivid Red, Custom Color*
Self Timer
Approx. 10-sec. delay, Approx. 2-sec. delay, custom*
*Delay time (0-15sec. (in one-second increments), 20/25/30 sec.) and number of shots (1-10 shots (in one-shot increments)) can be specified)
Wireless Control
Continuous Shooting
Approx. 3.3 shots/sec. (in P Mode)
Approx. 7.8 shots/sec. (in High-speed Burst mode)
Storage Media
SD Memory Card, SDHC memory Card, SDXC Memory Card , Eye-Fi
File Format
Design rule for camera file system, DPOF Version 1.1 compliant
Image Recording Format
Normal, Fine
JPEG Compression Mode
Still Image: Exif 2.3 (JPEG)
Video: MOV (Image: H.264; Audio: Linear PCM (stereo))
Number of Recording Pixels
Large: 4000 x 2248
Medium 1: 2816 x 1584
Medium 2: 1920 x 1080
Small: 640 x 360
Image data
Movie data
Playback Modes File
Still Images & Video:
Auto Rotate, Transition Effects, Scroll Display, Active Display, Rotate, Favorites, My Category, Smart Shuffle, Group Playback, Movie Digest, Filtered Playback, Slideshow
Erase Modes
Select image, select range, all images (all filtered images)
Computer Interface
USB 2.0 Hi-Speed USB (dedicated female connector with unified type of digital, audio and video) mini-B compatible.
Video Out
NTSC/PAL (dedicated connector (female) with unified type of digital, audio and video)
Mini-HDMI connector
Audio Out
Stereo (dedicated connector (female) unified type of digital, audio, and video)
Memory card slot; direct connection to Canon SELPHY Compact Photo Printers, PIXMA Inkjet Photo Printers and PictBridge-compatible printers via camera's USB 2.0 Hi-speed cable
Power Source
Battery Pack NB-9L, Compact Power Adapter CA-DC10 (included with AC Adapter Kit ACK-DC70)
Shooting Capacity
Approx. 170 shots
Playback Time
Approx. 4 hours
Operating Temperature
Operating Humidity
Dimensions (W x H x D)
3.90 x 2.32. x 0.86 in / 99.0 x 58.9 x 21.9 mm
Approx. 7.27 oz / 206 g (Including battery and memory card)
Approx. 6.46 oz / 183 g (camera body only)


text:
tartan button down shirt
by A.P.C.
Men's Size Chart
Product Details
Traditional style button down shirt in a blue and green tartan pattern. Featuring a button down collar, single chest pocket, slight curved hem and button cuff and placket.
• tailored fit
• 100% cotton
• machine wash cold
• imported

subset: commoncrawl


text:
Affordable Caricatures by Mark Odewald
Marlene K. Goodman-Caricatures With Personality
Caricatures by McGee
Home Team Caricature
Caricatures by Parody Prdctns
Adam Belmares Caricatures
A caricature artist will delight guests by quickly drawing their likeness! A caricature artist can also provide drawings and illustrations for books, comics, t-shirts and more! Search here for Caricature Artist in Chicago IL.


text:
Remember this?
"If you can't think of the best gift that has yet to be given, let me suggest a book. Books are great. Unlike electronics, they don't crash or freeze, they are incredibly tactile and the feeling of looking at a picture on a page is far superior to looking at one on a screen (it's the glossiness, I think).
I've got some fashion book choices for the various people in your life. Well, the people in your life who like fashion. For everyone else, I'd suggest a book token."
No? That's grand – that was part one of my Christmas gift guide – now on with part two…
1. For the Voguette, the woman who wants to be Nuclear Wintour, or Alexandra Schulman, or Franca Sozzani, and has the Mt. Everest of Vogues to prove it, I'd suggest you get a copy of Vogue: The Editor's Eye – a full review of which will be coming on Monday. Focusing on the role of the fashion editor through the latter half of the twentieth century to the present day, there are some really nice spreads that throw light (rightfully) on women like Babs Simpson, Polly Mellen and Tonne Goodman. You might not know who they are, but the Voguette definitely will.
Honourable mention – In Vogue: An Illustrated History of the World's Most Famous Fashion Magazine
via Getting Beat Like You Stole Something
2. For the (platonic) man friend who's looking to up his game sartorially, there are two things. First, give him a round of applause/packet of crisps for getting into personal style in a country where, except for a few inclusive pockets, it's not incredibly popular to do so. Second, give him a copy of Style and The Man by Alan Flusser. It's all about suits and tailoring, so there's nothing too avant-garde and there's absolutely zilch that Flusser doesn't know about knots, cuffs and how to get a good three piece made without compromise.
Honourable mention – Icons of Mens Style
3. For the street-style savvy friend who can't get enough of The Sart (I was going to title this one the 'street style slut' before I realised how insulting that was), the newest book by the aforementioned Sartorialist is a great bet. I wasn't a big fan of the first book, but The Sartorialist: Closer really showcases just how damn GOOD Scott Schuman has got at capturing the personality quirks as well as the outfits of his subjects.
Honourable mention – The Sartorialist (eh, if it's not broke don't fix it).


text:
Why are astronomers looking for planets around other stars? In this BrainPOP movie, Tim and Moby discuss exoplanets, and why they're so fascinating to the scientific community. You'll learn about why it's so difficult to observe them directly, and find out about the different methods for discovering new exoplanets indirectly. Tim will go over the concepts behind gravitational methods, including astrometry and the Doppler method, as well as a way to measure tiny changes in a star's light intensity. Plus, you'll find out about an exciting new way to observe exoplanets directly, by measuring their infrared radiation. So pull up a chair and see where the real ET lives!
Learn More:Are there any exoplanets with life on them?Can you tell me the names of some exoplanets?How many exoplanets are there?
See a Full List of Topics


text:
Où aller
Attractions touristiques Buengkan
View by :
Sort by :
Result per page :
Located in Ban Phu Ngoen, Amphoe Seka, this waterfall has its origin from Lam Huai Sanaen (refers to summit or excellence) and only has water in the rainy season. It is 100 meters wide and has two tie...Plus d'informations
Situated in Ban Don Siat, Tambon Ban Tong, Amphoe Seka, this waterfall comes from a stream of Huai Ka-am and flows along a high sandstone cliff spreading over a long line. The fall of the water causes...Plus d'informations
This waterfall only has water in the rainy season, but visitors will find that this tranquil and shady setting is worth visiting with a valley taking on deep bottom where a waterfall flows down the va...Plus d'informations
Located at Tambon Pho Mak Kaeng, this large beautiful waterfall features a ridge of the mountain made of stone cliffs and stone yard. From the stone yard, visitors can enjoy a picturesque view of Phu ...Plus d'informations
This waterfall only has water in rainy season, but is surrounded by timber forest with a great view of the northern Phu Wua. A walking trail takes you to the cascade seen along the narrow channel on t...Plus d'informations


text:
I noticed that Mathematica has a set of special 'Formal' characters such as
\[FormalB] , etc.. In the front end, it looks like a character with a dot above and below. It is not clear from the build-in help files how these characters are to be used.
Can anyone demonstrate?


text:
New home designs – Kirkdale Road
New home design – Jeet St Lucia
New home designs – Horseshoe bay House
New home designs – Grahams road residence
New home designs - Eumundi Lighthouse
New home designs – Bannisters Beach house
New home designs – Eco Home Winmalee
"The living area is on the first floor, and the family room is one level up, with a deck we use as our 'high use' outdoor area. We also wanted to develop the notion of a courtyard as a breathing space – on each level we look at the garden from a different perspective," he says.The courtyard has also helped Willett keep work and home life separate. "Walking across that small courtyard is a psychological going home, it's quite important," he says.
"It would've cost a lot more. It costs a huge amount to keep adding layers in a domestic house. [We've used a] gradual grading of lighter materials as it gets higher, starting with a brick veneer structure with timber floors, [while the] dormer uses timber Cyprus pine cladding," he says.An extendable awning over the second level deck makes this important outdoor space usable in hot weather, while pushing the stairs to the front of the house helps control heat inside.
"In summer the sun doesn't get into lower levels at all; it's quite a remarkable difference between the courtyard and the lower levels. People think we have air conditioning, but we simply use fans at the top levels to extract that hot air, and some small operable skylights," says Willett.
"Double glazing costs about 30 per cent more; we couldn't afford that. [On the busy street side] we chose a thicker laminated glass normally produced as a safety glass – it gives quite a good acoustic performance. As people walk from the noisy street into the room the sound drops significantly," he says.Willett also saved money by using a series of small structural nibs throughout.
"It allows you to have a braced system that's cheaper than steel portal frames, gives you environmental performance you want, and consistent storage space," he says.
This site certainly has all the information and facts I wanted about this subject and didn't know who to ask. payday loans
payday loans for military 25-Jun-2012 11:17 PM


text:
Rapper and producer Big Boi drops by the Red Bull Studio LA to perform his new single 'Apple of My Eye.'
Get a look at behind the scenes as one of the most inspiring artists of our generation hits Red Bull Studio LA for an elaborate recording session.
The final episode of Red Bull Music Academy's H∆SHTAG$ investigates how the Internet has broadened the definition of pop music.
Billy Corgan and company came, saw and rocked a packed Red Bull Sound Select stage (and the fans across the street).
Red Bull Thre3Style will host the highly anticipated 2013 U.S. National Finals on Friday, April 5 at Hollywood hotspot LURE. Six of the best DJs from across the nation will battle for the U.S....
Smashing Pumpkins, the seminal rock band fronted by Billy Corgan, will headline Red Bull Sound Select 120 Hours in Austin on Saturday.
The "Island Hopping" remix is a collaboration that was a long time coming. Stalley and Javelin first linked up back in 2009 at DD172 and this remix shows Javelin taking inspiration from Stalley's...
The latest episode of Red Bull Music Academy's H∆SHTAG$ series explores the microblogging site Tumblr and how it has helped spawn movements like seapunk and boosted rappers like Kilo Kish and Le1f.
Five bands, from surf rockers Beach Party in L.A. to shoegazers Heliotropes out of Brooklyn, are going to Austin, looking to break out.


text:
Madden NFL 13 gameplay screenshots released
New screenshots look great, but I need to know more about the gameplay Read More
New screenshots look great, but I need to know more about the gameplay Read More
Six "future stars" versions of top-class prospects will also be included Read More
Vote for the NHL 13 cover athlete and win a trip to the 2012 NHL Awards Read More
Tim Tebow in danger of losing to teammate Von Miller Read More
This week we reviewed Mass Effect 3, SSX, The Walking Dead, and more, and we delivered some more original editorial content Read More
This week we've got reviews for Street Fighter X Tekken, Asura's Wrath, and more. Plus GDC previews! Read More
GameZone discusses the important topics in the sports video game world Read More
Changes in management at Tiburon mean changes with Madden NFL 13 Read More
Not too much to cheer for with this month's sales numbers... Read More
Call of Duty, The Simpsons, and CastleMiner Z dominate the Xbox LIVE activity Read More
But how accurate was it? Read More
Plus $10 off on Madden NFL 12 for PS3, Xbox 360, or Wii Read More
EA SPORTS uses Madden NFL 12 technology to sim Super Bowl XLVI. Will it be the Eli-led Giants or Brady's Pats who take home the glory? Read More
In a Super Bowl XLVI rematch, it all comes down to a last minute field goal Read More
Final Online Franchise roster update for Madden NFL 12 to come after Super Bowl Read More
Amazon reveals its best-selling games of 2011 Read More
Xbox 360's strong year capped by more than $1.5 billion in sales for December 2011. Read More
It's back and it's on fire – even without the leg drops. Read More
Game industry sales for November rests pretty at $3 Billion Read More
Day 8 of the 19 Deals of Christmas is EA Sports Day. Read More


text:
10-11am in the 3rd floor Discovery Center
January 08, 2013
Discovery Hour is a weekly interactive activity hour for families with children under 6, with activities ranging from staff led games and storytelling, to scavenger hunts and crafts. No RSVP is needed, and the program is included in the price of admission. See you there!


text:
- Home
- News
- Sports
- Opinion
- Obituaries
- Features
- Special Sections
- Classifieds
- Public Notices
Forgot Password? | Not a User? Sign up
Trustees have approved a budget for Hardin Memorial Hospital they hope will allow the hospital to finish next fiscal year with positive revenue.
Predictions for the current fiscal year, which ends Sunday, show the hospital ending the year with a revenue loss of more than $3.2 million. That was after making more than $4.4 million the year before.
If you currently subscribe or have subscribed in the past to the The News Enterprise, then simply find your account number on your mailing label and enter it below.
Click the question mark below to see where your account ID appears on your mailing label.
|ZIP Code:


text:
Walt Disney World
Enjoy 1-Day FREE with the purchase of any 4 Day Magic Your Way Ticket...
Read More
Universal Studios SPECIAL
Enjoy 14 Days Unlimited Access into Universal Studios, Islands of Adventure and Wet n Wild. Read More
SeaWorld Orlando
Buy a Single Day SeaWorld Ticket and upgrade to 2nd Day for just $15.00... Read More
Orlando Flex Tickets Unlimited access to Universal Studios Fl,Islands of Adventure, SeaWorld, Busch Gardens, Aquatica, Wet n' Wild... Read More
We have worked with millions of people around the world to bring them discounted tickets for some of Orlando, Florida's most popular attractions. With over 17 years of experience as a family owned business we have the ability to meet any vacation needs when it comes to discounted tickets. As an Authorized-Contracted Discount ticket agency for Disney World, Universal Studios, Sea World and many other world famous attractions in Orlando you will be sure to find the best value for your money at any of these attractions as well as on tickets to the Kennedy Space Center Visitors Complex and many dinner shows throughout the area.
When it comes to vacationing you will want to spend your time with your family seeing the great attractions, not waiting in line to purchase tickets. Being a licensed ticket broker, we can offer you the best upgrades and discounts on tickets which will save you money compared to buying at the gate. Every ticket we sell is a real ticket, there are no vouchers or trade-ins that you will have to deal with. We believe our customers' information should be confidential; security and privacy are our top priorities. With this in mind, we utilize a highly secure online transaction system which provides a user friendly experience and insures the safety of our customers' personal information.
A vacation to Orlando should be a wonderful mix of dreams and adventures and we aim to make sure that your family enjoys all of the attractions that the Orlando area has to offer. You will be able to experience everything from the world famous Disney Parks to Sea World and Universal Orlando® Resorts, featuring Universal Studios Florida® and Universal's Islands of Adventure®. To make sure that your vacation is as simple and enjoyable as possible, we provide a one stop solution for your Orlando tickets and trip planning needs.
& Get a 5th Day Free!
One of the newest attractions in Orlando can be found at the Kennedy Space Center Visitors Complex. Explore Space Shuttle Atlantis in her new $100 million home and gain a better understanding of the wonders of space travel. You will have the chance to get up close and personal as you and your family witness one of history's most beloved space shuttle that NASA has provided. The price for this exhibit is included in your admission into the Kennedy Space Center Visitor Complex so that you will get as much value for your money as possible.
Click here to purchase your discount tickets today!
Discover endless action and unforgettable thrills at Orlando's first and only firearms attractions ‐ Machine Gun America™. Experience the ultimate automatic adrenaline attraction™. Choose from a variety of shooting experiences and don't miss out on a truly one-of-a-kind experience. Just minutes from Orlando!
Click here for details
HARRY POTTER, characters, names and related indicia are trademarks of and © Warner Bros. Entertainment Inc. Harry Potter Publishing Rights © JKR.
Universal elements and all related indicia ™ & © 2015 Universal Studios. All rights reserved


text:
Ithaca College Choir
The Ithaca College Choir, under the direction of Janet Galván, is recognized through its annual tour, performances at ACDA and MENC Conferences and international concerts as one of the most innovative ensembles at the collegiate level. This spring the Choir will perform in Alice Tully Hall in an exciting program of contemporary music called "Music of Our Time." The Choir portion of the program is called "Dancing Between Darkness and Light." The Choir was formerly under the direction of Lawrence Doebler.
The Ithaca College Choir has toured extensively on the East Coast, South and Mid-West United States and in 2002 performed in Ireland. The Choir has presented major concerts at the American Choral Directors Association in Providence, the Music Educators National Conference in Baltimore and Providence; Lincoln Center Avery Fisher Hall and Alice Tully Hall, Carnegie Hall, Symphony Space, St. Patrick's Cathedral, and Cooper Union in New York City; the Brooklyn Academy of Music in Brooklyn, the Troy Savings Bank in Troy, NY and the Strand Theatre in York, PA. In addition to the a cappella tradition, the choir has performed with the Cayuga Chamber Orchestra, the Ithaca College Orchestra and Chamber Orchestra and Wind Ensemble.
In each of the last thirty-six years, the Ithaca College Choir has premiered a work that premiered at the Ithaca College Composition Festival.


text:
Archive for the 'Bjorn Envall' tag
Class of '86- Saab 9000 Turbo
Saab's flagship 9000 was a bit controversial, from its model year 1986 introduction all the way through its 1998 swan song. The result of an aborted collaboration between Saab and Fiat – which would also spawn the peripherally related Fiat Chroma, Lancia Thema and Alfa Romeo 164, collectively known as the Type 4s – the 9000 was considered "too conventional" by hard-core Saabers used to the 99/900's wrap-around windshield and between-the-seats ignition key, and "too strange" by mainstream executive car buyers who couldn't equate a four-cylinder hatchback with luxury and performance. Those who looked beyond the hype were rewarded with what many Saab lovers consider to be the automaker's most underrated, well-rounded car of all time.
Styled by Giorgetto Giugiaro's Italdesign, with input from Saab's chief designer Björn Envall, the 9000 was launched in Turbo form, and it featured a transversely mounted four-cylinder engine, the first Saab so equipped since the original two-cylinder 92. It rode on a 105.2-inch wheelbase, which was vastly longer than the contemporary 900's (99.1-inches), despite the new car actually being shorter (and wider) than its older sibling.
Road & Track enjoyed the turbocharged and intercooled DOHC, 1,985cc 16-valve four-cylinder, which made 160 hp at 5,500 RPM and 188-lbs.ft. of torque at 3,000 RPM, noting that the five-speed-equipped tester sprinted to 60 in 7.6 seconds and completed the quarter mile in 15.6 seconds at 89.5 MPH. They wrote:
The new Swede exhibits better suspension tuning, feels tighter and more nimble and is quieter than the 900. The ride is exceptionally pleasant, particularly at highway speeds. In true Saab tradition, the 9000 is an extremely comfortable long-distance touring car that also tackles curvy roads with finesse and secure handling. And if the twisty bits happen to be at higher altitudes, the turbo becomes a bonus feature, maintaining useable power.
The impressive performance of the stock 9000 Turbo was proven with great elan when a team of cars broke numerous international speed records at Talladega in 1986.
That transversely mounted engine reaped major benefits for interior occupants, who found a surprising amount of room inside the 9000; in fact, upon introduction, it was one of only two cars sold in America to be classified by the EPA as having a "large" interior volume; the other was the limo-like Rolls-Royce Silver Spirit.
A traditional three-box, four-door sedan would arrive for 1989 in the form of the 9000 CD. This car brought a "slant nose" facelift that would be shared with five-door 9000s in 1991 and 1992, while a heavily revised 9000 CS would appear in 1993, bringing new front and rear styling, improved side impact protection and the mid-year introduction of the incomparable enthusiast favorite, the 9000 Aero.
The original 9000 Turbo starred in Saab Suite, a spectacular eight-minute film starring the automaker's hugely talented, very courageous Performance Driving Team.
There have been a surprising number of Saab 9000s in the Hemmings employee parking lot through the years, so we don't need to tell you where we stand on this car. It's your turn to chime in – do you feel that the Saab 9000 Turbo is a suitable member of the Class of 1986 fantasy garage? Or is it just another Vermont winter beater?


text:
- Musician's Friend Best Selection, Price & Service. Guaranteed.
Call our Gear Heads
at: 800-449-9128
Call our Gear Heads
at: 800-449-9128
A studio microphone with a retro look, warm sound, and is optimized for vocal recordings with the capsule of the legendary M 49 and U 47.
The Neumann TLM 49 is a large-diaphragm studio microphone with a cardioid directional characteristic and a warm sound. The TLM 49 is specially optimized for vocal performance. It is supplied as a set, with an elastic suspension.
The Neumann TLM 49's design is inspired by that of the legendary M 49 and M 50 microphones of the 1950s. Naturally the TLM 49 has the typical Neumann fine matte nickel finish. The sound design is also oriented toward that of the M 49 and the
By combining its retro look with proven Neumann transformerless circuit technology, this microphone ensures low self-noise and the use of high gain levels.
During the development phase, the sound was adjusted in extensive practical tests, so as to make the TLM 49 ideal particularly for vocal and speech recording. However, in addition, it is also suitable for instrumental applications in professional production studios and demanding home recordings.
Polar pattern
The large-diaphragm capsule of the TLM 49 provides a cardioid directional characteristic with a tendency toward supercardioid, due to the special capsule construction. Following the example of the M 49, high frequencies are more directional. The capsule diameter is 34 mm.
The front of the microphone is indicated by the red Neumann logo on the microphone body. The capsule is oriented so that the microphone is addressed from the front.
Acoustic features
The TLM 49 uses the famous K 47 capsule, which was also used in the M 49 and the U 47. The capsule has a linear frequency response up to the upper mid-range. Above 2 kHz there is a gentle presence boost up to 3dB.
The capsule is enclosed by a large microphone head grille, which is acoustically very open and is hence neutral with regard to the sound.
Electrical features
The letters TLM stand for "transformerless microphone". With TLM technology the usual output transformer is replaced by an electronic circuit.
As with traditional transformers, it ensures good common mode rejection, and prevents RF interference that may influence the balanced audio signal.
Noise signals which affect the balanced modulation line are therefore effectively suppressed. The microphone can operate at sound pressure levels of up to 114 dB without distortion, and provides a dynamic range of 102 dB (A-weighted).
Operational safety
The entire interior structure is mounted elastically, to prevent the transmission of structure-borne noise. In addition, the capsule is mounted with a rubber shock mount.
Due to the wide frequency response, the TLM 49 can also transmit extremely low-frequency signals without coloration. Of course this means that the microphone is also sensitive to noise signals such as vibration noise and wind noise in this frequency range. The TLM 49 is therefore supplied with the elastic suspension EA 3, which effectively protects the microphone from structure-borne noise. If the microphone is addressed at extremely close range, pop screen PS 15 or PS 20 a can be used in front of the microphone to provide protection against plosive sounds.
Requires phantom power.
TLM 49 Condenser Studio Microphone
Review Snapshot®by PowerReviews
Reviewed by 8 customers
Sort by
Best Uses
Comments about Neumann TLM 49 Condenser Studio Microphone:
I pondered for a year before spending this much on a mic but I should have bought it long ago. I use it primarily for acoustic guitar and vocals. I was using an Audio Technica AT4040 which is a good mic but no where near the clarity of this mic. When recording two or more vocals at once, each vocal stands out as if it were on a separate track. Excellent sound reproduction.
Best Uses
Comments about Neumann TLM 49 Condenser Studio Microphone:
Neumann can't make anything but magnificent microphones. It is big.
Comments about Neumann TLM 49 Condenser Studio Microphone:
I use it for mainly for my own vocals (male). But I also use it as an extra stereo mic for acoustics. I have compared it against the U87----and for me, it is softer and more character. Love this mic. Very, very dependable and useful mic.
Comments about Neumann TLM 49 Condenser Studio Microphone:
I'm a professional producer in Taiwan. And running this mic through an API512 pre going through Apogee convertors. This thing does just as much damage as the M 49 or other mics that cost about 3-5X the price.
Comments about Neumann TLM 49 Condenser Studio Microphone:
The beauty of this new generation of TLMs and specially the 49, is that when exposed to slightly higher spl it will create a odd harmonic (3rd mainly) distortion that will color before cracking, which means as vocalists get louder, a vintage tuby sound can be achieved. very cool. But don't be limited to it, it also sounds killer on acoustic guitars, woodwinds, Cello, Db Bass and so on
Comments about Neumann TLM 49 Condenser Studio Microphone:
I was scared to death to spend this much money on a microphone, but I'm soooo glad I did. It adds an unimaginable depth and warmth to your recordings. I got it primarily for vocals, but I've used it to record acoustic guitar and it sounded amazing as well. It's an expensive mic, but worth every penny.
Comments about Neumann TLM 49 Condenser Studio Microphone:
The studio tech that recorded my bands EP has two of these, and let me tell you they are amazing. He used them as room mics for the drums, for recording group vocal, and for recording guitars.
Comments about Neumann TLM 49 Condenser Studio Microphone:
I just recieved my nuemann tlm 49 a few hours ago and stoped recording just long enough to write a review. WOW! What a mic. I am using it on vocals pluged into a avalon 737 sp through a carvin analog 24 studio board to a alesis adat hd24xr. I have a few other med. priced tube mics in my studio that gave me good results , but this mic is taking my recoring to the next level.The warm tone is amazing.The avalon and this mic are a dynamic duo. kind of expensive for a project studio but worth it. One great sounding mic is better than a bin full of so so mics.
Our product catalog varies by country due to manufacturer restrictions. If you change the Ship-To country, some or all of the items in your cart may not ship to the new destination.


text:
Brush up on your tactics before heading into battle as Devil Survivor 2's remastered edition hits the Nintendo 3DS.
Views: 1,924 | Posted: 05/04/2015
Take a look at all the incredible indie games making their way to Wii U and 3DS!
Views: 2,475 | Posted: 04/02/2015
Battle fires and save lives in over 30 Fire & Rescue missions in Planes: Fire & Rescue.
Views: 1,667 | Posted: 11/05/2014
It's up to Bloom and her Winx friends to save the upcoming anniversary party at Alfea in Winx Club: Saving Alfea.
Views: 969 | Posted: 10/17/2014
Follow May in her quest to find her missing brother in May's Mysteries: The Secret of Dragonville.
Views: 651 | Posted: 10/15/2014
Help Dusty and his fearless fighters battle massive fires and learn what it takes to become a true hero in Planes: Fire & Rescue.
Views: 1,340 | Posted: 09/25/2014
Modify time to avoid all kinds of dangers in 99Seconds.
Views: 865 | Posted: 09/23/2014
Get your first look at gameplay in this trailer for Kirby: Canvas Curse!
Views: 10,191 | Posted: 06/10/2014
Nintendo's E3 digital event gets a little help from Robot Chicken.
Views: 39,644 | Posted: 06/10/2014
The classic RPG finally comes to Steam! When darkness cloaks the land, a band of adventurers must set out on an epic journey to bring light back to the world.
Views: 4,663 | Posted: 06/04/2014


text:
Blackberry and technology world go hand in hand in the world of business. Their products are designed to integrate documents across multiple devices for information sharing and development. Now the connection has been made between the tablet and cell phone with the help of the new Blackberry Bridge technology. The paperless office is that much closer to a reality.
Blue Ant Connect Voice Control Headset$69.99
Out of stock


text:
"Hansel And Gretel" OzOpera Tour Launch
Singers Louise Watts playing the role of a Hansel and Harriet... ニュース写真エンタメ総合,オーストラリア,シドニー,ニューサウスウェールズ州,ハンセル,パフォーマンス,ヘンゼルとグレーテル,人の役割,作曲家 エンゲルベルト フンパーディンク,子供,旅行,歌う,発表イベントPhotographer Patrick RiviereCollection: Getty Images Entertainment 2006 Getty ImagesSYDNEY, NSW - MARCH 03: Singers Louise Watts playing the role of a Hansel (L) and Harriet Marshall playing the role of Gretel perform in front of the Crown Street Primary school children during the OzOpera tour launch for Humperdinck's 'Hansel and Gretel' at The Opera Centre on March 3, 2006 in Sydney, Australia. Thousands of primary school children will see opera for the first time when Opera Australia's OzOpera heads off to perform its highly popular 50-minute version of Humperdinck's opera Hansel and Gretel in primary schools all over New South Wales. (Photo by Patrick Riviere/Getty Images)


text:
Saturday, 05/04/1991
Somerville Theatre, Somerville, MA
Set 1: Oh Kee PaThe Oh Kee Pa Ceremony > SuzySuzy Greenberg, Cavern > Reba, MSOMy Sweet One > SOAMeltSplit Open and Melt, GuelahGuelah Papyrus, Fluffhead > Mike'sMike's Song > HydrogenI Am Hydrogen > WeekapaugWeekapaug Groove
Set 2: Dog Log > Llama, Forbin'sColonel Forbin's Ascent[1] > MockingbirdFly Famous Mockingbird > Buried Alive > HoodHarry Hood, Horn > Rocky Top > Possum
Encore: Terrapin, Runaway Jim
Encore 2: GolgiGolgi Apparatus
[1] Guest horn player.
· L.A. Woman tease in Possum
Average Song Gap: 4.13
Performers: Trey Anastasio, Page McConnell, Jon Fishman, Mike Gordon
Notes: Forbin's featured a guest horn player dressed in a leopard-skin toga and a huge orange Mohawk. Hood was played in support of the Vermont Dairy Farmers. Possum contained an L.A. Woman tease from Trey. Terrapin was dedicated to "Marni." The Aquarium Rescue Unit was the opening act.
Song Distribution:
4 Lawn Boy
3 A Picture of Nectar
3 The Man Who Stepped into Yesterday
2 Junta
1 Stash
1 Rift
1 The White Tape
Songs by Debut Year:
This show was part of the "1991 Winter/Spring Tour."


text:
Utah Jazz v Boston Celtics
Palabras clave
Kevin Garnett of the Boston Celtics announced before the game against... Fotografía de noticiasBaloncesto,Basket-ball - NBA Pro,Boston - Massachusetts,Boston Celtics,Deporte,EE.UU.,Horizontal,Kevin Garnett,Massachusetts,Partido,TD Garden,Utah Jazz - Equipo de baloncestoPhotographer Brian BabineauCollection: National Basketball Association 2012 NBAEBOSTON - NOVEMBER 14: Kevin Garnett #5 of the Boston Celtics announced before the game against the Utah Jazz on November 14, 2012 at the TD Garden in Boston, Massachusetts. NOTE TO USER: User expressly acknowledges and agrees that, by downloading and or using this photograph, User is consenting to the terms and conditions of the Getty Images License Agreement. Mandatory Copyright Notice: Copyright 2012 NBAE (Photo by Brian Babineau/NBAE via Getty Images)


text:
Additional Programs
La Sierra University offers several distinct programs that compliment the mission of the university and further our commitment to the uniting of academic investigation, Christian faith, and service to others.
English Language and American Culture
Students from all over the world come to La Sierra University to learn to speak, read and write the English language. To learn more about our English as a Second Language program, click here.
La Sierra University is a national leader in the integration of service-learning into the undergraduate classroom. Service-learning is an educational strategy that incorporates community-based service into academic instruction to support the learning goals of a course. To learn more about our Service-Learning program, click here.
Study Abroad Experiences
At La Sierra, students are encouraged to engage in quarter, summer, or year-long study abroad opportunities offered around the world. In addition, study tour experiences take students and community members abroad during the summer months. To learn more about Study Abroad opportunities, click here.
University Studies
University Studies is La Sierra's comprehensive general education curriculum. It is rooted in the concept of liberal education as a formative and transformative process. To learn more about University Studies, click here.


text:
- Northern New York Newspapers
- Watertown
- Ogdensburg
- Massena-Potsdam
- Lowville
- Carthage
- Malone
- NNY Business
- NNY Living
- NNY Ads
The number of Jefferson County municipalities accepting online payments of town and county taxes is increasing from two to eight this year. The towns of Alexandria, Brownville, Clayton, Hounsfield, Rodman and Watertown join Ellisburg and Champion in offering the service.
Residents may pay via links on the towns websites or on the Jefferson County home page.
Paul J. Warneck, director of real property tax services for the county, said the resource, which initially was offered in only two towns as part of a pilot program, was a great success in its first year.
For 2013, it was offered to all 22 towns in the county. While only six additional towns signed up, Mr. Warneck said he expects the service to be popular, and hopes to go from eight to 15 towns in 2014.
According to Mr. Warneck, the debate about offering an online payment system based on credit and debit cards and e-checks has been going on for several years, often concentrating on how to structure the convenience fees charged by the companies that provide the transaction service.
According to a press release from Real Property Tax Services, for a Visa debit card, there is a flat fee of $3.95. Residents also may pay with MasterCard, Visa or Discover credit cards for a fee of 2.45 percent. E-checks are accepted for a fee of $1.75. Payments are handled by Value Payment Systems.
The Jefferson County treasurer is offering a similar service through Systems East Inc., Cortland, for the payment of back taxes and other fees. For payment with a debit or credit card, a 2.85 percent convenience fee is assessed, plus a 28 cent fixed fee. E-checks are accepted for a fee of $2.50.
In the private sector, companies offering electronic payment typically absorb the cost of the transaction in order to stoke sales by offering a variety of payment methods. They are able to do this by spreading the cost over a large number of customers.
In the countys case, where a smaller number of customers is involved, the taxpayer must pay the fee out of pocket to complete the transaction. It is called a convenience fee, whereby the user pays a small amount for the ease of paying online and avoiding a trip to the clerks office or the post office.
The service is expected to be particularly attractive to nonresident owners of property in waterfront towns such as Clayton and Alexandria, who no longer will have to go through the hassle of sending their payments by mail from far-off locations. It also is expected to be popular with residents of larger towns.
The convenience fee is less than the 3 percent fee charged by Real Property Tax Services for a plan that allows residents to pay their taxes in installments from Jan. 1 through March 15.
This is about offering as many options to the taxpayer as possible, Mr. Warneck said. The less delinquencies there are at the end of the collection period, the better off the county is.
According to Mr. Warneck, the use of electronic payment services is expected to proliferate throughout the county, with credit and debit cards eventually being accepted for tax maps and other ancillary services offered by county departments.
An ATM planned to be located in the building is expected to fill the gap where electronic payment methods are not accepted.
Property tax bills for the town and county levies will be in the mail on or before Tuesday.
They can be paid online at www.co.jefferson.ny.us. If residents experience problems with the service, they are asked to contact the office of Real Property Tax Services before reaching out to their town officials.
The city of Watertown will offer electronic payment of taxes, water and sewer bills and garbage collection bags by the end of January, according to City Comptroller James E. Mills.
The payments for the city also will be handled by Systems East at the same convenience fees as the county.
Thousands of readers like you have made Northern New York Newspapers the number one ranked website* for local news and sports coverage in the north country.
You can continue on to this article in a few seconds, or you can visit one of our websites:


text:
IMPORTANT: Please click "End Session" to clear your personal information. (Credit Card info is always hidden from view).End Session
Cookies are not enabled in your browser.
You must have Cookies enabled for the best experience on our site and to make a purchase.
Learn how to enable Cookies in your browser or call 1-800-426-8020 for assistance.
REFINE BY About Refinements
Perfect on their own in warmer weather, our short sleeve tops and t-shirts become versatile layering pieces as the weather cools. Pair a pretty printed tank or your favorite cardigan or blazer for a versatile look that spans the seasons.
29 items
Women's Quantum Short-Sleeve T-Shirt$60.00 $45.00
Women's Favorite Striped Henley Shirt$35.00-$40.00 $21.00-$24.00
Women's Lookout Short-Sleeve T-Shirt - Solid$30.00 $18.00
Women's Short-Sleeve Favorite V-Neck T-Shirt$20.00-$23.00 $12.00-$13.80
Women's Essential Slub Short-Sleeve V-Neck T-Shirt$25.00-$28.00 $15.00-$16.80
Women's Infinity Cap-Sleeve T-Shirt$30.00-$35.00 $18.00-$21.00
Women's Girl On The Go® 3/4-Sleeve Twist Top$40.00 $24.00
Women's Girl On The Go® Wrap Top$40.00 $20.00
Women's Favorite Long-Sleeve Crewneck T-Shirt$25.00-$28.00 $15.00-$16.80
Women's Daisy Short-Sleeve Wrap$50.00 $30.00
Women's Essential Slub Short-Sleeve Scoop-Neck T-Shirt$25.00-$28.00 $15.00-$16.80
Women's Essential Slub Long-Sleeve V-Neck T-Shirt$30.00-$35.00 $18.00-$21.00
Women's Essential Slub Long-Sleeve Scoop-Neck T-Shirt$30.00-$35.00 $18.00-$21.00
Women's Favorite Long-Sleeve V-Neck T-Shirt$25.00-$28.00 $15.00-$16.80
Women's Favorite 3/4-Sleeve Scoop-Neck T-Shirt$25.00-$28.00 $15.00-$16.80
Women's Short-Sleeve Favorite Crewneck T-Shirt$20.00-$23.00 $12.00-$13.80
Women's Incendiary 1/4-Zip Pullover Shirt$70.00-$80.00 $42.00-$52.50
Women's Resolution Short-Sleeve T-Shirt$30.00 $18.00
Women's Resolution V-Neck T-Shirt$30.00 $18.00
Women's Resolution Dolman-Sleeve Tunic$40.00 $24.00
Women's Novelty Crochet T-Shirt$40.00 $24.00
Women's Movement Freedom T-Shirt$50.00 $37.50
Women's Stine's Waffle Crew - Stripe$55.00 $41.25
Women's Stine's Waffle Henley - Solid$45.00-$50.00 $33.75-$37.50
Women's Favorite Long-Sleeve Crew T-Shirt - Stripe$30.00 $18.00


text:
Moderator: All Things Mods
Rowan Redbeard wrote:How long does it take for a gentleman pirate to get a cup of tea in this place? Do I need to draw my sword and threaten to cut off pasta shaped portions of people's anatomy?
OZ_Nick wrote:Yarr! Sorry 'bout that Cap'n Redbeard. Oi 'ave sent me cabin boy out ter get sum tea, we don't get much call fer it in 'ere. But don't worry, why not 'ave a Captain's Delight XO on the house, while ye wait?
Users browsing this forum: No registered users and 3 guests


text:
Science Friday® is produced by the Science Friday Initiative, a 501(c)(3) nonprofit organization.
Science Friday® and SciFri® are registered service marks of Science Friday, Inc. Site design by Pentagram; engineering by Mediapolis.
|For years, astronomers have been trying to locate the source of high-energy cosmic rays that hit the Earth's atmosphere. In new work published this week in the journal Science, researchers report that the most energetic cosmic rays they detected can usually be traced back to areas of the sky that contain nearby Active Galactic Nuclei, which are thought to be powered by supermassive black holes devouring large amounts of matter. The work was based on detailed observation of 77 extremely high energy cosmic ray events using the Pierre Auger Observatory in Argentina. In this segment, Ira and guests talk about the findings and what they might mean.


text:
|Número de publicación
|Tipo de publicación
|Número de solicitud
|Fecha de publicación
|19 Dic 2002
|Fecha de presentación
|7 May 2002
|Fecha de prioridad
|7 Mar 1994
|También publicado como
|Número de publicación
|John Patton, Linda Foster, Robert Platz
|Cesionario original
|Patton John S., Foster Linda S., Platz Robert M.
|Exportar cita
|BiBTeX, EndNote, RefMan
|Citas de patentes (5), Citada por (11), Clasificaciones (25), Eventos legales (2)
|Enlaces externos: USPTO, Cesión de USPTO, Espacenet
[0001] This application is a continuation-in-part of application Ser. No. 08/207,472, filed on Mar. 7, 1994, the full disclosure of which is incorporated herein by reference.
[0002] 1. Field of the Invention
[0003] The present invention relates generally to methods and compositions for the respiratory delivery of insulin to diabetic patients. More particularly, the present invention relates to the pulmonary delivery of dry powder insulin preparations for rapid systemic absorption through the lungs.
[0004] Insulin is a 50 amino acid polypeptide hormone having a molecular weight of about 6,000 which is produced in the pancreatic β-cells of normal (non-diabetic) individuals. Insulin is necessary for regulating carbohydrate metabolism by reducing blood glucose levels, and a systemic deficiency causes diabetes. Survival of diabetic patients depends on the frequent and long-term administration of insulin to maintain acceptable blood glucose levels.
[0005] Insulin is most commonly administered by subcutaneous injection, typically into the abdomen or upper thighs. In order to maintain acceptable blood glucose levels, it is often necessary to inject insulin at least once or twice per day, with supplemental injections of rapid-acting insulin being administered when necessary. Aggressive treatment of diabetes can require even more frequent injections, where the patient closely monitors blood glucose levels using home diagnostic kits. The present invention is particularly concerned with the administration of rapid acting insulins which are able to provide serum insulin peaks within one hour and glucose troughs within 90 minutes.
[0006] The administration of insulin by injection is undesirable in a number of respects. First, many patients find it difficult and burdensome to inject themselves as frequently as necessary to maintain acceptable blood glucose levels. Such reluctance can lead to non-compliance, which in the most serious cases can be life-threatening. Moreover, systemic absorption of insulin from subcutaneous injection is relatively slow, frequently requiring from 45 to 90 minutes, even when fast-acting insulin formulations are employed. Thus, it has long been a goal to provide alternative insulin formulations and routes of administration which avoid the need for self-injection and which can provide rapid systemic availability of the insulin.
[0007] A variety of such alternative insulin administration roots have been proposed, including intranasal, intrarectal, and intravaginal.
[0008] While these techniques avoid the discomfort and poor compliance associated with subcutaneous injection, they each suffer from their own limitations. Intrarectal and intravaginal are inconvenient, uncomfortable, and the latter is not available to the entire population of diabetics. Intranasal delivery would be convenient and probably less objectionable than injection, but requires the use of potentially toxic "penetration enhancers" to effect passage of insulin across the nasal mucosa, which is characterized by a thick epithelial layer which is resistant to the passage of macromolecules of particular interest to the present invention is pulmonary insulin delivery where a patient inhales an insulin formulation and systemic absorption occurs through the thin layer of epithelial cells in the alveolar regions of the lung. Such pulmonary insulin delivery appears to provide more rapid systemic availability than does subcutaneous injection and avoids the use of a needle. Pulmonary insulin delivery, however, has yet to achieve widespread acceptance. Heretofore, pulmonary delivery has been most often accomplished through nebulization of liquid insulin formulations, requiring the use of cumbersome liquid nebulizers. Moreover, the aerosols formed by such nebulizers have a very low insulin concentration, necessitating a large number of inhalations to provide an adequate dosage. Insulin concentration is limited due to the low solubility of insulin in suitable aqueous solutions. In some cases1 as many as 80 or more breaths may be required to achieve an adequate dosage, resulting in an administration time from 10 to 20 minutes, or more.
[0009] It would be desirable to provide improved methods and compositions for the pulmonary delivery of insulin. It would be particularly desirable if such methods and compositions were sufficiently convenient to permit self-administration even away from home and were able to deliver a desired total dosage with a relatively low number of breaths, preferably fewer than ten. Such methods and compositions should also provide for rapid systemic absorption of the insulin, preferably reaching a serum peak within 45 minutes or less and a resulting glucose trough within about one hour or less. Such rapid acting formulations will preferably be suitable for use in aggressive treatment protocols where injection of intermediate and long-acting insulin can be reduced or eliminated. The compositions of the present invention should also be stable, preferably consisting of a concentrated dry powder formulation.
[0010] 2. Description of the Background Art
[0011] The respiratory delivery of aerosolized aqueous insulin solutions is described in a number of references, beginning with Gansslen (1925) Klin. Wochenschr. 4:71 and including Laube et al. (1993) TAMA 269:2106-21-9; Elliott et al. (1987) Aust. Paediatr. J. 23:293-297; Wigley et al. (1971) Diabetes 20:552-556. Corthorpe et al. (1992) Pharm Res 9:764-768; Govinda (1959) Indian J. Physiol. Pharmacol. 3:161-167; Hastings et al. (1992) J. Appl. Physiol. 73:1310-1316; Liu et al. (1993) JAMA 269:2106-2109; Nagano et al. (1985) Jikeikai Med. J. 32:503-506; Sakr (1992) Int. J. Phar. 86:1-7; and Yoshida et al. (1987) Clin. Res. 35:160-166. Pulmonary delivery of dry powder medicaments, such as insulin, in a large particle carrier vehicle is described in U.S. Pat. No. 5,254,330. A metered dose inhaler (MDI) for delivering crystalline insulin suspended in a propellant is described in Lee and Sciara (1976) J. Pharm. Sci. 65:567-572. A MDI for delivering insulin into a spacer for regulating inhalation flow rate is described in U.S. Pat. No. 5,320,094. The intrabronchial administration of recombinant insulin is briefly described in Schlüter et al. (Abstract) (1984) Diabetes 33:75A and Köhler et al. (1987) Atemw. Lungenkrkh. 13:230-232. Intranasal and respiratory delivery of a variety of polypeptides, including insulin, in the presence of an enhancer, are described in U.S. Pat. No. 5,011,678 and Nagai et al. (1984) J. Contr. Rel. 1:15-22. Intranasal delivery of insulin in the presence of enhancers and/or contained in controlled release formulations are described in U.S. Pat. Nos. 5,204,108; 4,294,829; and 4,153,689; PCT Applications WO 93/02712, WO 91/02545, WO 90/09780, and WO 88/04556; British Patent 1,527,605; Rydén and Edman (1992) Int. J. Pharm. 83:1-10; and Björk and Edman (1988) Int. J. Pharrm. 47:233-238. The preparation and stability of amorphous insulin were described by Rigsbee and Pikal at the American Association of Pharmaceutical Sciences (AAPS), Nov. 14-18, 1993, Lake Buena Vista, Fla. Methods for spray drying polypeptide, polynucleotide and other labile drugs in a carrier which forms an amorphous structure which stabilize the drug are described in European patent application 520 748.
[0012] According to the present invention, methods and compositions for the aerosolization and systemic delivery of insulin to a mammalian host, particularly a human patient suffering from diabetes, provide for rapid absorption into blood circulation while avoiding subcutaneous injection. In particular, the methods of the present invention rely on pulmonary delivery of insulin in the form of a dry powder. Surprisingly, it has been found that inhaled dry insulin powders are deposited in the alveolar regions of the lung and rapidly absorbed through the epithelial cells of the alveolar region into blood circulation. Thus, pulmonary delivery of insulin powders can be an effective alternative to administration by subcutaneous injection.
[0013] In a first aspect of the present invention, insulin is provided as a dry powder, usually but not necessarily in a substantially amorphous state, and dispersed in an air or other physiologically acceptable gas stream to form an aerosol. The aerosol is captured in a chamber having a mouthpiece, where it is available for a subsequent inhalation by a patient. Optionally, the dry powder insulin is combined with a pharmaceutically acceptable dry powder carrier, as described in more detail below. The insulin powder preferably comprises particles having a diameter less then 10 μm, more preferably less than 7.5 μm, and most preferably below 5 μm, usually being in the range from 0.1 μm to 5 μm. Surprisingly, it has been found that the dry powder insulin compositions of the present invention are absorbed in the lung without the use of penetration enhancers such as those required for absorption through the nasal mucosa and upper respiratory tract.
[0014] In a second aspect, the present invention provides insulin compositions consisting essentially of dry powder insulin having an average particle size below 10 μm which may be combined with dry powder pharmaceutical carriers. The insulin composition is preferably free from penetration enhancers and comprises particles having a diameter less than 10 μm, preferably less than 7.5 μm, and most preferably below 5 μm, usually being in the range from 0.1 μm to 5 μm. Usually, the insulin dry powder will have from 5% to 99% by weight insulin in the composition, more usually from 15% to 80%, in a suitable pharmaceutical carrier, usually a carbohydrate, an organic salt, an amino acid, peptide, or protein, as described in more detail hereinafter.
[0015] In a third aspect of the present invention, insulin dry powders are prepared by dissolving insulin in an aqueous buffer to form a solution and spray drying the solution to produce substantially amorphous particles having a particle size less than 10 μm, preferably less than 7.5 μm, and most preferably below 5 μm, usually being in the range from 0.1 μm to 5 μm. Optionally, the pharmaceutical carrier is also dissolved in the buffer, to form a homogeneous solution, wherein spray drying of the solution produces individual particles comprising insulin, carrier buffer, and any other components which were present in the solution. Preferably the carrier is a carbohydrate, organic salt, amino acid, peptide, or protein which produces a substantially amorphous structure upon spray drying. The amorphous carrier may be either glassy or rubbery and enhances stability of the insulin during storage. Advantageously, such stabilized formulations are also able to effectively deliver insulin to the blood stream upon inhalation to the alveolar regions of the lungs.
[0016] A further understanding of the nature and advantages of the invention will become apparent by reference to the remaining portions of the specification and drawings.
[0017]FIG. 1 is a schematic illustration of a system for aerosolizing a dose of insulin according to the method of the present invention.
[0018]FIG. 2 is a schematic illustration of a patient inhaling an aerosolized dose of insulin from the system of FIG. 1.
[0019]FIGS. 3A and 3B are graphs illustrating the absorption of recombinant human insulin in rats and resulting glucose response following aerosolization of three different Do4 dry powder formulations. Each point represents the mean value from three different rats. At zero time, the dry powder aerosol generator was turned on. Aerosolization was complete at 5 min, 14 min and 20 min for the 87% insulin/citrate, 20% insulin-mannitol/citrate and 20% insulin-raffinose/citrate powders, respectively. Animals were fasted overnight.
[0020]FIGS. 4A and 4B are graphs illustrating mean serum time-concentration insulin and glucose profiles, respectively comparing aerosol and subcutaneous administrations in cynomolgus monkeys. The mean value for three monkeys is reported for the aerosol group, and the mean value for four monkeys is reported for the subcutaneous group.
[0021]FIG. 5A is a graph illustrating the mean insulin concentration over time for subcutaneous injection (∘) and for inhalation of three puffs () in humans.
[0022]FIG. 5B shows the mean glucose concentration corresponding to the insulin concentrations of FIG. 5A.
[0023]FIG. 6A is a graph illustrating serum insulin concentration over time as a result of subcutaneous injection (∘) and three puffs of aerosol administration () in humans.
[0024]FIG. 6B is a graph illustrating the serum glucose levels corresponding to the insulin levels in FIG. 6A.
[0025]FIGS. 7A and 7B provide a comparison of the intersubject variability of serum insulin (7A) and glucose levels (7B) for subcutaneous administration (∘) and aerosol administration ().
[0026]FIGS. 8A, 8B, and SC show rpHPLC chromatograms of a human insulin.
[0027]FIG. 8A is a chromatograph of an insulin standard stressed in 10 mM HCl at 25° C., showing human insulin eluting at 23.87 minutes desamido insulin eluting at 30.47 minutes.
[0028]FIG. 8B shows a similar chromatogram of a human a insulin standard. FIG. 8C shows a similar chromatogram of reconstituted, spray-dried insulin formulation prepared according to the present invention.
[0029]FIG. 9 shows an ultraviolet spectra of an insulin formulation before and after spray drying. No light scattering was observed in the visible spectrum, indicating ill that insulin did not aggregate during the spray drying process.
[0030] According to the present invention, insulin is provided as a dry power. By "dry powder" it is meant that the moisture content of the powder is below about 10% by weight, usually below about 5% by weight, and preferably being below about 3% by weight. By "powder," it is meant that the insulin comprises free flowing particulates having a size selected to permit penetration into the alveoli of the lungs, preferably being less than 10 μm in diameter, preferably less than 7.5 μm, and most preferably less than 5 μm, and usually being in the range from 0.1 μm to 5 μm in diameter.
[0031] The present invention is based at least in part on the unexpected observation that dry powder insulins are readily and rapidly absorbed through the lungs of a host. It was surprising that dry powder insulins could reach the alveolar region of the lungs, as water-soluble drugs such as insulin particles are known to be hygroscopic. See, e.g. Byron, ed., Respiratory Drug Delivery, CRC Press, Boca Raton (1990), p. 150. Thus, it would have been expected that as the particles passed through the airways of the lung (which has a relative humidity in excess of 99% at 37° C.), the individual particles would have a tendency to absorb water and grow to an effective particle size larger than the 10 μm upper limit of the present invention. If a substantial fraction of the insulin particles were larger than the target size range, it would be expected that the particles would deposit within the central airways of the lungs rather than the alveolar region, thus limiting delivery and subsequent systemic absorption. Moreover, the fluid layer over the epithelial cells of the lungs is very thin, usually a fraction of the diameter of the insulin powders being delivered. Thus, it was unpredictable prior to the present invention whether the dry insulin particles would dissolve upon deposition within the alveolar regions of the lungs. Surprisingly, the dry insulin powders are apparently able to both penetrate into the alveolar regions of the lungs and dissolve once they have deposited within the alveolar region of the lung. The dissolved insulin is then able to cross the epithelial cells into circulation.
[0032] It is presently believed that the effective absorption of insulin results from a rapid dissolution in the ultrathin (<0.1 μm) fluid layer of the alveolar lining. The particles of the present invention thus have a mean size which is from 10 to 50 times larger than the lung fluid layer, making it unexpected that the particles are dissolved and the insulin systemically absorbed in a rapid manner. Indeed, as shown in the Experimental section hereinafter, the dry insulin formulations of the present invention can provide even more rapid serum insulin peaks and glucose troughs than afforded by subcutaneous injection, which is presently the most common form of administration. An understanding of the precise mechanism, however, is not necessary for practicing the present invention as described herein.
[0033] Preferred compositions according to the present invention will be substantially free from penetration enhancers. "Penetration enhancers" are surface active compounds which promote penetration of insulin (or other drugs) through a mucosal membrane or lining and are proposed for use in intranasal, intrarectal, and intravaginal drug formulations. Exemplary penetration enhancers include bile salts, e.g., taurocholate, glycocholate, and deoxycholate; fusidates, e.g., taurodehydrofusidate; and biocompatible detergents, e.g., Tweens, Laureth-9, and the like. The use of penetration enhancers in formulations for the lungs, however, is generally undesirable because the epithelial blood barrier in the lung can be adversely affected by such surface active compounds. Surprisingly, it has been found that the dry powder insulin compositions of the present invention are readily absorbed in the lungs without the need to employ penetration enhancers.
[0034] Insulin dry powders suitable for use in the present invention include amorphous insulins, crystalline insulins, and mixtures of both amorphous and crystalline insulins. Dry powder insulins are preferably prepared by spray drying under conditions which result in a substantially amorphous powder having a particle size within the above-stated range. Alternatively, amorphous insulins could be prepared by lyophilization (freeze-drying), vacuum drying, or evaporative drying of a suitable insulin solution under conditions to produce the amorphous structure. The amorphous insulin so produced can then be ground or milled to produce particles within the desired size range. Crystalline dry powder insulins may be formed by grinding or jet milling of bulk crystalline insulin. The preferred method for forming insulin powders comprising particulates in the desired size range is spray drying, where pure, bulk insulin (usually in a crystalline form) is first dissolved in a physiologically acceptable aqueous buffer, typically a citrate buffer having a pH in the range from about 2 to 9. The insulin is dissolved at a concentration from 0.01% by weight to 1% by weight, usually from 0.1% to 0.2%. The solutions may then be spray dried in conventional spray drying equipment from commercial suppliers, such as Buchi, Niro, and the like, resulting in a substantially amorphous particulate product.
[0035] The dry insulin powders may consist essentially of insulin particles within the requisite size range and be substantially free from any other biologically active components, pharmaceutical carriers, and the like. Such "neat" formulations may include minor components, such as preservatives, present in low amounts, typically below 10% by weight and usually below 5% by weight. Using such neat formulations, the number of inhalations required for even high dosages can be substantially reduced, often to only a single breath.
[0036] The insulin powders of the present invention may optionally be combined with pharmaceutical carriers or excipients which are suitable for respiratory and pulmonary administration. Such carriers may serve simply as bulking agents when it is desired to reduce the insulin concentration in the powder which is being delivered to a patient, but may also serve to enhance the stability of the insulin compositions and to improve the dispersability of the powder within a powder dispersion device in order to provide more efficient and reproducible delivery of the insulin and to improve handling characteristics of the insulin such as flowability and consistency to facilitate manufacturing and powder filling.
[0037] Suitable carrier materials may be in the form of an amorphous powder, a crystalline powder, or a combination of amorphous and crystalline powders. Suitable materials include carbohydrates, e.g., monosaccharides such as fructose, galactose, glucose, D-mannose, sorbose, and the like; disaccharides, such as lactose, trehalose, cellobiose, and the like; cyclodextrins, such as 2-hydroxypropyl-β-cyclodextrin; and polysaccharides, such as raffinose, maltodextrins, dextrans, and the like; (b) amino acids, such as glycine, arginine, aspartic acid, glutamic acid, cysteine, lysine, and the like; (c) organic salts prepared from organic acids and bases, such as sodium citrate, sodium ascorbate, magnesium gluconate, sodium gluconate, tromethamine hydrochloride, and the like; (d) peptides and proteins, such as aspartame, human serum albumin, gelatin, and the like; (e) alditols, such as mannitol, xylitol, and the like. A preferred group of carriers includes lactose, trehalose, raffinose, maltodextrins, glycine, sodium citrate, tromethamine hydrochloride, human serum albumin, and mannitol.
[0038] Such carrier materials may be combined with the insulin prior to spray drying, i.e., by adding the carrier material to the buffer solution which is prepared for spray drying. In that way, the carrier material will be formed simultaneously with and as part of the insulin particles. Typically, when the carrier is formed by spray drying together with the insulin, the insulin will be present in each individual particle at a weight percent in the range from 5% to 95%, preferably from 20% to 80%. The remainder of the particle will primarily be carrier material (typically being from 5% to 95%, usually being from 20% to 80% by weight), but will also include buffer(s) and may include other components as described above. The presence of carrier material in the particles which are delivered to the alveolar region of the lung (i.e., those in the requisite size range below 10 μm) has been found not to significantly interfere with systemic absorption of insulin.
[0039] Alternatively, the carriers may be separately prepared in a dry powder form and combined with the dry powder insulin by blending. The separately prepared powder carriers will usually be crystalline (to avoid water absorption), but might in some cases be amorphous or mixtures of crystalline and amorphous. The size of the carrier particles may be selected to improve the flowability of the insulin powder, typically being in the range from 25 μm to 100 μm. Carrier particles in this size range will generally not penetrate into the alveolar region of the lung and will often separate from the insulin in the delivery device prior to inhalation. Thus, the particles which penetrate into the alveolar region of the lung will consist essentially of insulin and buffer. A preferred carrier material is crystalline mannitol having a size in the above-stated range.
[0040] The dry insulin powders of the present inventions may also be combined with other active components. For example, it may be desirable to combine small amounts of amylin or active amylin analogues in the insulin powders to improve the treatment of diabetes. Amylinis a hormone which is secreted with insulin from the pancreatic β-cells in normal (non-diabetic) individuals. It is believed that amylin modulates insulin activity in vivo, and it has been proposed that simultaneous administration of amylin with insulin could improve blood glucose control. Combining dry powder amylin with insulin in the compositions of the present invention will provide a particularly convenient product for achieving such simultaneous administration. Amylin may be combined with insulin at from 0.1% by weight to 10% by weight (based on the total weight of insulin in a dose), preferably from 0.5% by weight to 2.5% by weight. Amylin is available from commercial suppliers, such as Amylin Corporation, San Diego, Calif., and can be readily formulated in the compositions of the present invention. For example, amylin may be dissolved in aqueous or other suitable solutions together with the insulin, and optionally carriers, and the solution spray dried to produce the powder product.
[0041] The dry powder insulin compositions of the present invention are preferably aerosolized by dispersion in a flowing air or other physiologically acceptable gas stream in a conventional manner. One system suitable for such dispersion is described in copending application Ser. No. 07/910,048, which has been published as WO 93/00951, the full disclosures of which are incorporated herein by reference. Referring to FIG. 1 herein, dry, free-flowing insulin powder is introduced into a high velocity air or gas stream, and the resulting dispersion introduced into a holding chamber 10. The holding chamber 10 includes a mouthpiece 12 at an end opposite to the entry point of the air powder dispersion. The volume of the chamber 10 is sufficiently large to capture a desired dose and may optionally have baffles and/or one-way valves for promoting containment. After a dose of the insulin powder has been captured in chamber 10, a patient P (FIG. 2) inhales on the mouthpiece 12 to draw the aerosolized dispersion into his lungs. As the patient P inhales, make-up air is introduced through a tangentially oriented air inlet port 14, whereby the air flows in a generally vortical pattern to sweep the aerosolized insulin from the chamber into the patient's lungs. The volume of the chamber and the aerosolized dose are such that a patient is able to completely inhale the entire aerosolized insulin dose followed by sufficient air to ensure that the insulin reaches the lower alveolar regions of the lung.
[0042] Such aerosolized insulin powders are particularly useful in place of subcutaneous injections of rapid acting insulin in the treatment of diabetes and related insulin-deficiencies. Surprisingly, it has been found that the aerosol administration of dry powder insulin results in significantly more rapid insulin absorption and glucose response than is achieved by subcutaneous injection. Thus, the methods and compositions of the present invention will be particularly valuable in treatment protocols where a patient monitors blood glucose levels frequently and administers insulin as needed to maintain a target serum concentration, but will also be useful whenever systemic insulin administration is required. The patient can achieve a desired dosage by inhaling an appropriate amount of insulin, as just described. The efficiency of systemic insulin delivery via the method as just described will typically be in the range from about 15% to 30%, with individual dosages (on a per inhalation basis), typically being in the range from about 0.5 mg to 10 mg. Usually, the total dosage of insulin desired during a single respiratory administration will be in the range from about 0.5 mg to 15 mg. Thus, the desired dosage may be effective by the patient taking from 1 breath to 4 breaths.
[0043] The following examples are offered by way of illustration, not by way of limitation.
[0044] Materials and Methods
[0045] Materials
[0046] Crystalline human zinc insulin, 26.3 Units/mg, (Lilly Lot #784KK2) was obtained from Eli Lilly and Company, Indianapolis, Ind. and found to be >99% pure as measured by rpHPLC. USP mannitol was obtained from Roquette Corporation (Gurnee, Ill.). Raffinose was purchased from Pfanstiehl Laboratories (Waukegan, Ill.). Sodium citrate dihydrate, USP, ACS and citric acid monohydrate USP were obtained from J. T. Baker (Phillipsburg, N.J.).
[0047] Powder Production
[0048] Insulin powders were made by dissolving bulk crystalline insulin in sodium citrate buffer containing excipient (mannitol, or raffinose, or none) to give final solids concentration of 7.5 mg/ml and a pH of 6.7±0.3. The spray dryer was operated with an inlet temperature between 110° C. to 120° C. and a liquid feed rate of 5 ml/min, resulting in an outlet temperature between 70° C. and 80° C. The solutions were then filtered through a 0.22 μm filter and spray dried in a Buchi Spray Dryer to form a fine white amorphous powder. The resulting powders were stored in tightly capped containers in a dry environment (<10% RH).
[0049] Powder Analyses
[0050] The particle size distribution of the powders was measured by liquid centrifugal sedimentation in a Horiba CAPA-700 Particle Size Analyzer following dispersion of the powders in Sedisperse A-11 (Micromeritics, Norcross, Ga.). The moisture content of the powders was measured by the Karl Fischer technique using a Mitsubishi CA-06 Moisture Meter.
[0051] The integrity of insulin before and after powder processing was measured against a reference standard of human insulin by redissolving weighed portions of powder in distilled water and comparing the redissolved solution with the original solution put into the spray dryer. Retention time and peak area by rpHPLC were used to determine whether the insulin molecule had been chemically modified or degraded in process. UV absorbance was used to determine insulin concentration (at 278 nm) and presence or absence of insoluble aggregates (at 400 nm). In addition, the pHs of the starting and reconstituted solutions were measured. The amorphous nature of the insulin powder was confirmed by polarizing light microscopy.
[0052] Rat Aerosol Exposures
[0053] Rat experiments were conducted in an aerosol exposure room. Female rats (280-300 gm) were fasted overnight. Animals (21-24/experiment) were placed in Plexiglas tubes and mounted into a 48 port, nose-only aerosol exposure chamber (In-Tox Products, Albuquerque, N. Mex.). Airflow to the breathing zone was maintained at 7.2-9.8 liters/minute and removed by vacuum so that there was a slight negative pressure (−1.5 cm H2O) in the chamber as measured by a magnahelic gauge. Aerosol exposure times were between 5-20 minutes depending on how much powder was fed into the chamber. Powders were fed by hand into a small Venturi nozzle which dispersed the powder particles to form a fine aerosol cloud. The Venturi nozzle was operated at a pressure in excess of 15 psig, and the air flow was set at 7.2 l/min to 9.8 l/min. The Venturi nozzle was fitted into the bottom of a clear Plexiglas dispersion chamber (750 ml) which passed the aerosol directly into a nose-only exposure chamber.
[0054] Rat Aerosol Chamber Calibration
[0055] The concentration of the powder at the breathing zone was measured by taking multiple, timed filter samples at the breathing zone with In-Tox filter holders at a vacuum flow of 2 liters/min. The chamber was calibrated both with and without animals. Powder mass was determined gravimetrically. The particle size of the powders at the breathing zone was measured with cascade impactor (In Tox Products) placed at a breathing hole and operated at a flow of 2 liters/min. Powder mass on each stage was determined gravimetrically.
[0056] Each powder test utilized 21-24 rats and the aerosol exposures lasted 5-20 minutes. Three rats were killed at 0 time and then at −7, 15, 30, 60, 90, 120, 180, and 240 minutes after the termination of the aerosol exposure. Animals were anesthetized, their abdomens opened, and a large blood sample was drawn from the ventral aorta. The animals were then killed by cervical dislocation.
[0057] Blood was allowed to clot at room temperature for 30 minutes and then centrifuged for 20 minutes at 3500 rpm in serum separator tubes. Serum was either analyzed immediately or frozen at −80° C. until analysis. As soon as possible (0-7 min) after the termination of the aerosol dosing, 3 rats were killed, their blood drawn and their lungs lavaged with six 5 ml rinses of phosphate buffered saline (PBS). The amount of insulin in the final pooled lavage sample was used as the aerosol dose for the rat in calculations of bioavailability.
[0058] Primate Exposure System
[0059] Young, wild-captured, male cynomolgus monkeys strain Macaca fascicularis (2-5 kg) (Charles River Primates, Inc.) were used for the primate aerosol studies (3-4 animals/group). The animals were either subcutaneously injected with Humulin (Eli Lilly, Indianapolis, Ind.) or exposed to a powder aerosol of insulin. Each animal was placed in a head-only exposure unit to provide a fresh supply of the test atmosphere at an adequate flow rate (7 L/min) to provide minimum oxygen requirements of the animal. The animals were restrained in a chair-like apparatus which placed them in an upright sitting position. The hoods were clear allowing the animals complete visualization of their environment. An indwelling catheter was placed in the leg so that blood samples could be taken at any time. The monkeys were fully awake during the whole procedure and appeared to be calm. Primate blood was treated the same as rat (see above).
[0060] The primate aerosol exposure system included a breath monitor that allowed quantification of the amount of air inhaled by each monkey. This value, coupled with measurements of the concentration of insulin in the inspired air allowed the calculation of exactly how much insulin was inhaled by each animal.
[0061] Human Trials
[0062] Insulin was administered to 24 normal human subjects subcutaneously as well as by inhalation of aerosolized dry insulin powders. Each subcutaneous injection consisted of 10.4U of Humulin R, 100 U/ml (Eli Lilly, Indianapolis, Ind.). The dry insulin powders were amorphous and prepared by spray drying as described above with 20% by weight mannitol excipient. Doses (5 mg) of the insulin dry powder were dispersed in a high-velocity air stream to produce a fine aerosol that was captured in a chamber. Each subject inhaled the aerosol powder by taking a slow, deep breath of each aerosol bolus or "puff." Powder was administered in three puffs (for a dosage of 31.9U). Serum insulin and glucose levels were determined over time, as described below.
[0063] Serum Assays
[0064] Serum insulin levels in rats, primates, and humans were determined using Coat-A-Count radio immunoassay kits for human insulin (Diagnostic Products Corporation, Los Angeles, Calif.). Standard curves were run with every batch of samples. The sensitivity of the assay was approximately 43 pg/ml. The within assay variability (%CV) is <5%. Glucose assays were performed by California Veterinary Diagnostics, Inc. in West Sacramento, Calif. using the Glucose/HK Reagent System Pack for the Boehringer Mannheim/Hitachi 747 Analyzer. The within assay variability (%CV) is <3%.
[0065] In the rate experiments, relative bioavailabilities of the aerosol were calculated by comparing the dose adjusted, immunoreactive insulin (IRI) area under the curve (AUC) of the concentration-time profile with that obtained from subcutaneous injection. In rats the total lavaged insulin mass was used as the aerosol dose. Some insulin is absorbed before the lungs can be lavaged so the dose estimated by this technique is probably a slight underestimate of the total deposited dose. No corrections for this presumed loss were made.
[0066] In the monkey experiments, relative bioavailabilities were calculated similar to the rats above except that instead of using lavaged lung insulin as the aerosol dose, the total amount of insulin inhaled was used. In the rats, only material deposited in the lungs, not insulin deposited in the nasal passages and throat, was included in the dose estimate. In the monkeys, all insulin that entered the animals was included in the dose estimate.
[0067] Results of Insulin Absorption in Rats
[0068] All of the insulin powders used in the animal studies had particle sizes (mass median diameters) ranging between 1-3 μm and moisture contents <3%. The insulin purity of the powders as measured by rpHPLC was >97%. Representative chromatographs of the 20% insulin formulation are shown in FIG. 8C. The powders yielded a clear solution upon reconstitution with pure water with an ultraviolet absorbance value <0.01 at 400 nm and a pH of 6.7±0.3. Representative ultraviolet (UV) spectra for the 20% insulin formulation are shown in FIG. 9.
[0069] The following three insulin powder formulations were tested in rats as aerosols in the In-Tox 48 port, exposure chamber.
[0070] 1. 87.9% insulin; 11.5% sodium citrate; 0.6% citric acid.
[0071] 2. 20% insulin; 66% mannitol: 12.4% sodium citrate: 0.6% citric acid.
[0072] 3. 20% insulin; 66% raffinose; 12.4% sodium citrate: 0.6% citric acid.
[0073] Table 1 lists the key measurements in the three different rat exposure studies including characterizations of the aerosol at the breathing zone and chamber operating conditions. A fraction of the powder fed into the venturi nozzle reached the breathing zones of the rats (34%-67%) because of losses in the walls due to impaction and incomplete dispersion of the powder during powder feed. The particle size of the aerosol at the breathing zone, however, was ideal for pulmonary deposition (1.3-1.9 μm) and was somewhat smaller than the original formulation particle size (2.0-2.8 μm) due to selective loss of the larger particles in the animal exposure chamber.
TABLE 1 Rat Aerosol Exposure Measurements 20% Insulin 20% Insulin 88% Insulin Mannitol Raffinose Chamber Flow Rate 7.2 L/min 9.6 L/min 9.8 L/min Powder Mass Median 2.2 μm 2.8 μm 2.0 μm Diameter (MMD) Powder Fed into Chamber 70 mgs 255 mgs 260 mgs Powder Feed Time 5 min 14 min 20 min Powder at Breathing Zone 40 mgs 171 mgs 88 mgs Insulin at Breathing Zone 35 mgs 34 mgs 18 mgs % Total Powder at Breathing Zone 57% 67% 34% Mass Median Aerodynamic 1.1 mg/L 1.3 mg/L 0.45 mg/L Diameter (MAD) Particle Size at Breathing Zone 1.4 μm 1.9 μm 1.3 μm Insulin Recovered in Lavage 30.7 ± 5.2 μg 12.7 ± 6.9 μg 31.6 ± 12.9 μg Serum Insulin AUC (ng min/ml) 104 201 150
[0074] Table 2 shows the rat serum insulin and glucose results from the three aerosol and one SC study. FIGS. 3A and 3B show the serum immunoreactive insulin (IRI) concentration-time profiles and the serum glucose concentration-time profiles for the three formulations administered by aerosol. Table 3 presents the insulin tmax, and the glucose tmin from the different studies as well as the relative bioavailability of the aerosol compared to SC injection.
TABLE 2 Serum Insulin and Glucose Results in Rats Serum Insulin Serum Glucose Time (pg/ml ± l S.D.) (mg/dl ± l S.D.) Formulation Route (min) n = 3rats/timept n = 3rats/timept 88% Insulin Aerosol 0 230 ± 184 106 ± 12 (Aerosol exposure Aerosol 12 1020 ± 312 114 ± 10 completed at minute 5) Aerosol 21 165 ± 768 81 ± 10 Av. Dose = 31 μg/rat Aerosol 36 876 ± 764 66 ± 7 Aerosol 66 684 ± 416 62 ± 15 Aerosol 96 568 ± 128 65 ± 10 Aerosol 126 564 ± 260 73 ± 11 Aerosol 186 712 ± 140 93 ± 5 20% Insulin-Mannitol Aerosol 0 476 ± 56 165 ± 18 (Aerosol exposure Aerosol 22 1476 ± 428 117 ± 15 completed at minute 14) Aerosol 35 2480 ± 892 101 ± 19 Av. Dose = 13 μg/rat Aerosol 57 1204 ± 64 64 ± 13 Aerosol 87 1084 ± 396 63 ± 17 Aerosol 117 664 ± 180 105 ± 38 Aerosol 147 1228 ± 416 108 ± 22 Aerosol 207 676 ± 100 119 ± 33 20% Insulin-Raffinose Aerosol 0 426 ± 97 157 ± 37 (Aerosol exposure Aerosol 27 2948 ± 2816 139 ± 46 completed at minute 20) Aerosol 42 1504 ± 592 181 ± 11 Av. Dose = 32 μg/rat Aerosol 57 1272 ± 496 124 ± 45 Aerosol 87 852 ± 164 128 ± 17 Aerosol 117 604 ± 156 124 ± 9 Aerosol 147 532 ± 172 172 ± 12 Aerosol 207 556 ± 100 218 ± 34 20% Insulin-Mannitol Subcutan 0 360 ± 140 107 ± 5 Dose = 30 μg Subcutan 15 14200 ± 3160 53 ± 2 Insulin/rat Subcutan 30 10160 ± 720 24 ± 5 Subcutan 60 11000 ± 1080 28 ± 6 Subcutan 90 2440 ± 1160 25 ± 7 Subcutan 120 3520 ± 840 49 ± 3 Subcutan 180 1280 ± 800 40 ± 17 Subcutan 240 400 ± 260 77 ± 34
TABLE 3 A Comparison of Aerosol and Subcutaneous (SC) Insulin in Animals Rat Rat Monkey Rat Aerosol Aerosol Aerosol Rat Aerosol 20% Insulin 20% Insulin Monkey 20% Insulin SC 88% Insulin Mannitol Raffinose SC Mannitol Insulin Max* 15 min 16 min 21 min 17 min 15 min 30 min Glucose Min.* 30 min 31 min 43 min 37 min 45 min 45 min Glucose Drop 77% 42% 62% 21% 45% 73% Rel Bicavail. 100% 10%** 44%** 14%** 100% 12%***
[0076] All three formulations provided rapid absorbing insulin to the rats systemic circulation (FIGS. 3A and 3B). The bioavailability and glucose response were higher for the 20% insulin/mannitol powder (Table 3), although without performing many replicate experiments, it is uncertain if the difference was significant.
[0077] Primate Results
[0078] A dose identical to what was used in the human trial (0.2 U/kg, ˜27 μg/monkey) was injected into four monkeys to provide the SC data with which to compare the aerosol results (FIGS. 4A and 4B). Table 4 shows the monkey aerosol exposure data. Table 5 shows the mean serum insulins and glucoses for the aerosol exposure and the subcutaneous study. The aerosol dose yielded a robust insulin and glucose response (high dose). FIG. 4 shows a comparison of the mean serum insulin profiles from the two aerosol and one SC study. From the AUCs of these profiles the relative bioavailability of the aerosol insulin was calculated to be 12%.
TABLE 4 Monkey Aerosol Exposure Data Est. Est. Grav. Avg Inhaled Inhaled Est. filter Aerosol Inhaled Aerosol Insulin Body Insulin AUC Mass Conc. Volume Mass Mass Wt. Dose (ng min/ Animal ID (mg) (μg/L) (L) (μg) (μg) (Kg) (μg/kg) ml) #1, 23-46 1.07 178 8.96 1597 320 3.92 81.5 347 #2, 23-48 1.01 168 19.98 3363 673 3.81 176.6 1196 #3, 122-55 0.97 162 14.68 2373 475 4.1 115.7 739 489 ± 178
[0079] Human Results
[0080] The comparative results between respiratory delivery and subcutaneous injection are set forth in Table 5 below. Respiratory aerosol delivery resulted in more rapid absorption (peak at 20 minutes) than injection (peak at 60 minutes) with a more rapid glucose response (trough at 60 minutes) than with injection (trough at 90 minutes). Reproducibility was as good if not better with aerosol than with injection in both insulin and glucose response. Injection doses were carefully adjusted for weight, aerosol doses were not. Biological activity of aerosol insulin, based on glucose response, relative to injection was 28-36%. Bioavailability of aerosol insulin, based on area-under-the-insulin curve, relative to injection was 22.8% for the 3 puff group.
TABLE 5 Serum Insulin and Glucose Results in Humans INSULIN Relative Increase Bio- Dose/ in Serum availability Injection Dose in Insulin Time of Based on Subject #s or Blister Subject* μU/ml Maximum Insulin AUC 1-24 10.4 U 10.4 U 5.8-20.9 60 min 100.0% (SC Injection) 7-24 76.0 U 31.9 U 6.1-28.5 20 min 22.8% (3 puffs) GLUCOSE Drop Relative in Mean Bioactivity Serum Based on Glucose mg/dl Time of Glucose Subject #s mg/dl drop Minimum % SC Drop 1-24 93.6-64.9 28.7 90 min 100% 100% (SC Injection) 7-24 91.8-67.6 24.2 60 min 84.3% 27.4% (3 puffs)
[0081] The results of the human trials are further presented in FIGS. 5A-5B. FIG. 5A shows mean serum insulin over time for subcutaneous injection (∘), inhalation (3 puffs, ). Mean serum glucose levels are similarly presented in FIG. 5B. Insulin peaks and glucose troughs are shown in FIGS. 6A and 6B, respectively, while intersubject variability in serum insulin and glucose are presented in FIGS. 7A and 7B, respectively.
[0082] In addition, the shallow inspirations (tidal breathing) of the monkeys during the aerosol exposures do not represent the optimal breathing maneuver for deep lung deposition. A higher bioavailability was observed in humans (Table 5), as expected, when the optimum breathing maneuver was used and the aerosol bolus was taken by oral inhalation rather than by nasal inhalation.
[0083] Although the foregoing invention has been described in some detail by way of illustration and example, for purposes of clarity of understanding, it will be obvious that certain changes and modifications may be practiced within the scope of the appended claims.
|Patente citada
|Fecha de presentación
|Fecha de publicación
|4 May 1936
|28 Mar 1939
|American Box Board Co
|Título no disponible
|Título no disponible
|Título no disponible
|Título no disponible
|Patente citante
|Fecha de presentación
|Fecha de publicación
|20 May 2005
|29 Jun 2010
|Quadrant Drug Delivery Limited
|Solid dose delivery vehicle and methods of making same
|20 May 2005
|24 Ago 2010
|Quadrant Drug Delivery Limited
|Solid dose delivery vehicle and methods of making same
|20 May 2005
|31 Ago 2010
|Quadrant Drug Delivery Limited
|Solid dose delivery vehicle and methods of making same
|21 Jun 2001
|1 May 2012
|Novartis Pharma Ag
|Engineered particles and methods of use
|3 Sep 2010
|21 Ago 2012
|Novartis Ag
|Respiratory dispersion for metered dose inhalers comprising perforated microstructures
|22 Jul 2005
|26 Mar 2013
|Novartis Ag
|Formulation for pulmonary administration of antifungal agents, and associated methods of manufacture and use
|24 Oct 2008
|29 Abr 2014
|Novartis Ag
|Phospholipid-based powders for drug delivery
|31 Oct 2007
|6 May 2014
|Novartis Ag
|Pulmonary delivery of aminoglycoside
|6 Dic 2012
|4 Nov 2014
|Novartis Ag
|Stable metal ion-lipid powdered pharmaceutical compositions for drug delivery
|20 May 2005
|15 Dic 2005
|Roser Bruce J
|Solid dose delivery vehicle and methods of making same
|15 Nov 2007
|20 May 2009
|Novo Nordisk A/S
|Pharmaceutical compositions for pulmonary or nasal delivery of peptides
|Clasificación de EE.UU.
|424/46, 514/5.9, 514/6.9, 514/1.2
|Clasificación internacional
|Clasificación cooperativa
|Clasificación europea
|25 Feb 2003
Owner name: NEKTAR THERAPEUTICS, CALIFORNIA
Free format text: CHANGE OF NAME;ASSIGNOR:INHALE THERAPEUTIC SYSTEMS, INC.;REEL/FRAME:013525/0753
Effective date: 20030113
|7 Ene 2009
Owner name: NOVARTIS PHARMA AG,SWITZERLAND
Free format text: ASSIGNMENT OF PATENT RIGHTS;ASSIGNOR:NEKTAR THERAPEUTICS;REEL/FRAME:022071/0001
Effective date: 20081231


text:
Moderator: Other Stuff Mods
The Grauniad wrote:The BBC did not give details about the nature of the court order, or which judge made the ruling.
It's a shame we had to have Paul McCartney ...
DavidH wrote:It's a shame we had to have Paul McCartney ...
Be grateful - it could have been Cliff Richard.
black bart wrote:The Hollow Crown on BBC has been outstanding...it encompasses the four Shakespearean Plays: Richard II, Henry IV Part 1 and 2 and finally Henry V. Jeremy Irons is Henry IV and there is an all star cast throughout including Patrick Stewart as John of Gaunt and Tom Hiddleston as Prince Hal.
daftbeaker wrote:I am not watching The Riots: In their own Words because some knobend of a judge has banned it from being shown.The Grauniad wrote:The BBC did not give details about the nature of the court order, or which judge made the ruling.
Quite possibly (and I have no evidence for this, it's just a suggestion) because the judge, legal basis and reasoning are not allowed to be made public. I'm still willing to bet Mr inJustice Eady's involved somewhere.
black bart wrote:This weeks Doctor Who was absolutely cracking. It also featured the best joke ever on Dr Who when the Doctor asked the hilarious Mark Williams (Fast Show) have you got any vegetable matter on you? Mr Williams answered, with his hands fumbling in his pockets: "only my balls" *
*Golf Balls as it happens
Return to "Books and Authors, Films and Directors"
Users browsing this forum: No registered users and 4 guests


text:
You have no items in your shopping cart.
Knife Block Sets
Knife block sets from WÜSTHOF, Mercer, ZWILLING J.A. HENCKELS, and Ginsu are available in kits ranging from 5 to 36 pieces. These knife sets include chef's knives, santoku knives, paring knives, and more*, all contained within a handsome hardwood block. Knife blocks are attractive for display purposes and are useful tools for protecting your knife investments.
*Actual knife selection varies by model
*Actual knife selection varies by model


text:
Lucis Trust / Home / Money and Spiri... / New York
New York
The Lucis Trust and its service activities foster and promote the universal principles and values upon which a just and holistic world order must be based. All the activities of the Lucis Trust, including the training provided by the Arcane School and the offerings of the Service Activities, Triangles and World Goodwill, are made available without charge. This work is financed entirely by donations. The Lucis Trust is a tax-exempt, non-profit educational organization (501c3 status).
You can support the Lucis Trust by:
Without bequests and legacies, the Lucis Trust would not be able to continue its work. If you are considering including a legacy to the Lucis Trust in your will, you are strongly advised to ask an attorney to prepare a will for you.
The following is a suggested form for bequests:
I hereby bequeath the sum of $_______ to the Lucis Trust, a non-profit tax-exempt corporation with offices at 120 Wall Street, New York, New York 10005, for the support of its general activities* without restriction as to particular use.
*or alternatively: to the Lucis Trust for the support of the Arcane School, Triangles action, book publishing, or World Goodwill action.
It is useful to keep a brochure about the Lucis Trust with your will or trust document in order to provide your Executors with information they may need. This saves delay.
You do not have to tell us if you are leaving a legacy to the Lucis Trust in your will, but it would be helpful to us to know, as it may affect our long term financial planning. Information about the amount of your legacy is not required, but we would appreciate receiving for our records a copy of the relevant portion(s) of the will relating to your intended gift.
Lucis Trust
Tel: +1 (212) 292-0707 -- Fax: +1 (212) 292-0808


text:
Summer 2011: Bahamas Trip
• Averaged 3.8 points and 2.8 rebounds in four games off the bench.
• Made 6-of-7 shots from the field and 3-of-5 free throw attempts.
• Had nine points and five rebounds in eight minutes in a 12-point win over Commonwealth Giants, including tip-in at end of second quarter that gave the Jays the lead for good.
2010-11: Junior at Creighton
• Played 16 minutes during 11 different games, all as a reserve.
• Played a minute in the season-opening win over Alabama State (Nov. 12), but did not record a statistic.
• Shot 1-for-3 from the floor while finishing with two points and a rebound in four minutes vs. Kennesaw State, including some first half minutes (Nov. 26).
• Appeared in three CBI games off the bench.
• Named to Creighton University Dean's List and the NABC Honors Court for his academic work.
2009-10: Sophomore at Creighton
• Made his debut on Nov. 22 against UALR, grabbing a rebound and making one free throw.
• Also played final 85 seconds against Houston Baptist (Dec. 22).
• Played final 42 seconds of CIT win over Fairfield (March 22), grabbing an offensive board and assisting on Matthew Dorwart's first career basket.
• Played less than a minute in both exhibition games but did not record any statistics.
• Named to Creighton Dean's List and MVC Academic Honor Roll.
2008-09: Freshman at Creighton
• Did not play.
• Practiced with Creighton's team that finished 27-8 and tied for the MVC regular-season title.
• Earned a spot on Creighton's Dean's List.
Thompson Valley High School
• Earned four letters in baseball, three in basketball and one in tennis.
• Seven-time all-conference pick, including twice in hoops and four times in baseball.
• Averaged 14.8 points and 8.8 rebounds per game as a senior while shooting 50 percent from the field, 45 percent from three-point range and 71 percent from the line.
• Had a high game of 26 points as a senior.
• All-City basketball pick by the Loveland Reporter.
• As a senior was named first-team all-state in baseball.
• Ranked 15th in his class of 325 with a GPA of 4.0 to pick up academic excellence awards each year.
• Graduated with an Honors diploma.
• Was nominated for the Wendy's High School Heisman.
• Team played in the Northern Colorado Conference in Colorado's class 4A.
• Senior year tennis team won conference and advanced to state.
• Team advanced to state in baseball during his freshman and sophomore seasons.
• Played for coaches Carey Duval and Paul Arrington in basketball, Jay Klagge in tennis and Jay Denning in baseball.
More About Derek
Full Name: Derek James Sebastian
Birthday: June 9, 1990
Birthplace: Fort Collins, Colo.
Parents: Jim & Lori Sebastian
Sister: Alyssa (23)
Major: Education, Natural Science emphasis
Did You Know?: Father ran track at Wyoming and Idaho State
Career Ambition: Science teacher and basketball coach
Nickname: "D"
Why Creighton: Strong science school
Favorite TV Show: Deadliest Catch
Hobbies: Tennis, ping pong, sand volleyball, 4-wheeling
Favorite Spot on Campus: Basketball team room
Favorite Sports Team: Denver Nuggets
Favorite Athletes: Blake Griffin and Chauncey Billups
Favorite Sports Memory: Won conference first season playing tennis in high school and made state
Awards & Honors
Creighton University Dean's List
Creighton University Dean's List
MVC Academic Honor Roll
Creighton University Dean's List
MVC Academic Honor Roll
NABC Honors Court
Career Highs
2 vs. Kennesaw State 11/26/10
Field Goals
1 vs. Kennesaw State 11/26/10
Field Goal Attempts
3 vs. Kennesaw State 11/26/10
3-Point Field Goals
3-Point Field Goals Attempted
Free Throws
1 vs. Arkansas-Little Rock 11/22/09
Free Throws Attempted
2 vs. Arkansas-Little Rock 11/22/09
1 (3x), last vs. Kennesaw State 11/26/10
1 vs. Fairfield 3/22/10
4 vs. Kennesaw State 11/26/10
|Loveland, Colo.
|High School:
|Thompson Valley


text:
Free agent righthander Jair Jurrjens, who was not tendered by the Braves after a rough 2012 season, has agreed to a deal with the Orioles, CBSSports.com has learned.
Jurrjens will receive a $1.5 million base on a Major League deal and can bring his totalk to $4 million with incentives.
Orioles GM Dan Duquette did a superb job finding pitching gems last winter, and this is another of the low-risk variety. Jurrjens went 3-4 with a 6.89 ERA with Atlanta and spent much of the year in the minors.