text:
Situated on the beach in the friendly San Antonia Bay area, the La Sirena Apartments are close to the shops, bars and restaurants of the area and just steps away from the nearest sandy beach. The apartments are a popular choice for younger couples and families looking to enjoy the daily and nightly entertainment in the summer and are also a great choice in the autumn where the town becomes a quieter place to relax that older visitors can enjoy with enough activities in the area all year around to keep you entertained. The apartments were totally reformed and modernized in 2004 and are an ideal place for younger couples and families looking to enjoy the fabulous beaches and nightly entertainment in the summer as well as a quieter place to relax that older visitors can enjoy in the autumn. The complex consist of several spacious studio apartments with self-catering facilities that are ideal for couples, families and groups of any age group looking to explore all the area has to offer. Guests can enjoy a selection of pleasant facilities at the apartments all designed to help make your stay more comfortable and relaxing with an outdoor swimming pool located at the back of the hotel where it is quieter and a large solarium next to it. There is a great caf�-bar, Kiki that overlooks the sea and features regular entertainment and music in the evenings and there is a games room where you can play billiards and video games. The reception area is always available to help with any request you might have as well as offering useful services such currency exchange and safety deposit boxes or can provide helpful information on what places to visit in the area.
The hotel lies very close to the Es Pouet beach, which makes for the perfect place to spend the day soaking up the sun and enjoying sea breezes or alternatively if you are feeling a bit more active then there are plenty of water sports to try out such as windsurfing and scuba diving. If you wish to explore some of the great nearby locations such as the Ibiza old town, Formentera or the Ibiza Castle and cathedral, then you will find it easy to do so by either the regular buses or boat trips available in the town. There is a wide choice of shops, eateries and restaurants available day and night just a short stroll from the apartments and if you are looking for a lively nightlife then you need only take a short walk down the promenade to find many of San Antonia's bars and clubs.
Distance from Airport:
15 miles
There are 30 individual studio apartments that make up the complex and each one can accommodate up to 3 adults or 2 adults and 2 children with single beds and a sofa bed. All the apartments also come with self-catering facilities with a kitchenette that includes a microwave and fridge. Each apartment comes with a spacious balcony and is well-equipped with all the essential amenities you would need including air conditioning, satellite TV, telephone and a complete bathroom with bath/shower and WC.
Transfer time:
25 minutes
Location and Resort:
The property is just over a mile from the centre of San Antonio and the Yacht Club. There are a total of 30 studio apartments and all have a part view or full view of the sea. San Antonio has plenty of restaurants, shops and bars and a number of trendy boutiques for when lazing on the beach gets too much.
Eating and Drinking:
The La Kiki Caf� at the apartments offers a great selection of light meals and drinks to keep you going through the day and is well known in the area for its evening entertainment of music, shows and games.
Swimming pools:
The apartments feature an outdoor swimming that is suitable for both adults and children and there is a large solarium next to the pool.
Right choice:
The La Sirena Apartments are the right choice for anyone looking for spacious and affordable accommodation in the more relaxed area of San Antonia Bay, with plenty to do and see in the area for a fun-filled holiday in Ibiza.
Suitable for:
Families and Couples
Hotel Air Conditioning Public Areas
Hotel Beachfront
Hotel Cafe/Snack Bar
Hotel Couples
Hotel Courtesy Room
Hotel Currency Exchange
Hotel Families
Hotel Internet Access
Hotel Lifts
Hotel Luggage Storage
Hotel Outdoor Pool
Hotel Parking
Hotel Pool/Billiard Table
Hotel Reception Limited Opening
Hotel Separate Children's pool
Hotel WiFi
Room Air Conditioning Room
Room Bath/Shower
Room Fridge
Room Kitchenette
Room Microwave
Room Safe Local Charge
Room Satellite TV
Room Telephone


text:
Who should the Jets Buyout?
View Single Post
Join Date: Mar 2012
Location: Vancouver
Posts: 19,517
vCash: 500
Originally Posted by
The buyouts wouldn't be for 2012-13. They'd be for the 2013-14 season. Antro and Hainsey are both UFA's at the end of June this year. According to Capgeek, the only players signed for 2013-14 are:
Kane (5 years remaining at $5.25 MM each / Buyout cost $9.5 MM)
Jokinen (1 year remaining at $4.5 MM / Buyout cost $3.0 MM)
Ladd (3 years remaining at $4.4 MM each / Buyout cost $9.0 MM)
Slater (2 years remaining at $1.6 MM each / Buyout cost $2.13 MM)
Thorburn (1 year remaining at $866K / Buyout cost $600K)
Byfuglien (3 years remaining at $5.2 MM each / Buyout cost $11.67 MM)
Enstrom (5 years remaining at $5.75 MM each / Buyout cost $19.17 MM)
Stuart (1 year remaining at $1.7 MM / Buyout cost $1.2 MM)
Pavelec (4 years remaining at $3.9 MM each / Buyout cost $5.42 MM)
Scheifele (2 or 3 years remaining at $1.59 MM each)
Klingberg (1 year remaining at $870K)
Telegin (2 years remaining at $698K)
Melchiori (2 years remaining at $672K)
Chiarot (2 years remaining at $618K)
Sol (1 year remaining at $578K)
And the last 6 players on that list are all on two-way deals that don't count against the cap and pay them $55K - $70K when they're down in St. John's.
So everyone else is either a UFA or RFA at the end of this season. I don't think buyouts are going to be a priority for the Jets. I think it's a bit of an issue that the team has only 9 NHLers signed for next season.
Well I think you could probably consider Wheeler, Burmistrov, Little and Bogosian all but signed... so 13... bit better???
And most likely same for Postma and Machacek...
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subset: commoncrawl


text:
A woman walking in a beautiful floral garden, thinking of its patterns and the patterns of her romance, has her life violently ripped apart by another pattern - war.
©2001 K. Anderson Yancy (P)2001 K. Anderson Yancy
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text:
Beside presenting the cameo appearances by Miley and Penelope, the video manages to shed some light on the plot as it features more details on the major characters' lives.
Warner Bros. Pictures has debuted the first full-length trailer for "Sex and the City 2". Making its way out via Yahoo! Movies, the video is narrated by Carrie Bradshaw Preston while the scenes keep showing what happens to the four female best friends two years after the end of the first film.
Escaping from their hectic daily activities, Carrie, Samantha Jones, Miranda Hobbes Brady, and Charlotte York Goldenblatt fly to Abu Dhabi for one-week trip. While following the pleasures enjoyed by the women, the video gives a quick look at cameo appearances by Penelope Cruz and Miley Cyrus.
Serving as the follow up to 2008 "Sex and the City", "Sex and the City 2" has Sarah Jessica Parker, Kim Cattrall, Cynthia Nixon and Kristin Davis returning to reprise their respective roles. Directed by Michael Patrick King, the forthcoming drama comedy is slated to arrive in the U.S. on May 27, a day earlier than the original release date.


text:
Need Appliance Repair Help? Ask a Technician for Answers ASAP
Hello and welcome to just answer my name is ***** ***** I will be the one to assist you. What is the model number of your unit?
Ok so you said it will no longer rotate I assume you mean spin? Have you checked the water pump? I am having a hard time pulling up your model with that model number can you double check that for me?
Ok that makes a world of difference. Sorry if the site offered you the phone call it was not from me. So then the turn plate is not turning. No it certainly would not be a water pump I thought this was a washer at first.
Does it light up inside when you start it?
It is a possibility that your fuse may have blown. The fuse is typically located next to the magentron and can visually be inspected in the back of the unit to see if its blown.
If you can check the fuse out and let me know if its blown I am here to assist you if you need me. Sorry about the confusion with thinking this was a washer.
Were you able to check the fuse yet?


text:
Fallout 4 Free Download
Fallout 4 Free Download
Located on this page is a Fallout 4 Free Download! Scroll down below for additional information to the game, minimum PC specifications, steps for installation, and a mega.nz download to the game itself! ↓
About the Game…
Fallout 4 was developed by Bethesda Game Studios and published by Bethesda Softworks. Its release took place on November 2015, and was available for purchase and download on Windows PC. It was also released on console platforms, such as Xbox and Playstation. The game is set in the year 2287 in Boston, after a global nuclear war that took place 210 years before. The concurring theme within the game is a hybrid between post-apocalyptic and retro-future, thus creating a unique gaming experience that many have never seen in any video game title before. The game also incorporates aspects of 1940's and 1950's culture and aesthetics, thus adding to the retro-futuristic ambiance of the game. Players have the luxury of free-roaming anywhere on the map, as well as have the luxury to switch between a first-person and third-person point of view when playing. As opposed to previous editions of the Fallout series, Fallout 4 consists of new features, such as a layered armor system, a larger dialogue system, a base-building, and a detailed crafting system that incorporates all lootable items within the game.
Minimum PC Specifications
Before you proceed with your Fallout 4Â Free Download: It is best to check if your PC can run the game. The minimum PC requirements to run the game are listed below:
- Operating System: Windows 7/8/10.
- CPU:Â Intel Core i5-2300 @ 2.8 GHz, AMD Phenom II X4 945 @ 3.0 GHz.
- GPU: NVIDIA GTX 550 Ti  @ 2GB, AMD Radeon HD 7870 @ 2GB.
- Hard Drive Space: 30GB.
Steps for Download & InstillationÂ
Before starting your Fallout 4 Free Download: Remember to disable any form of antivirus before download [yes, that includes window defender too]. Failure in doing so can cause issues in running the program, after download and installation. All downloads are 100% clean and do not contain any viruses!
- Â Click the download to be redirected to Mega.
- Â Once your on Mega, click the "download through your browser link" and wait for the download to begin. If your download does not begin, click here for help.
- Once the download is completed, close your internet browser. Then click start and enter in your downloads folder. Locate the zip file to the game and drag it down to your desktop.
- Right click on the zip file, and click "extract to Fallout 4". To do this, you will need WinRAR. If you don't have WinRAR, click here.
- Once the files are done extracting, there should be a new folder on your desktop. Open it, and locate the "setup" file. Double click it, then click run.
- Â A "Check MD5" window should pop up. Leave it alone and let it check the MD5 files. Once its finished, a setup window should pop up.
- On the setup window, keep clicking next. Then click install, and wait for the game to fully install.
- Â Once the games done installing, click finish. AÂ shortcut to the game should appear on your desktop. Double click on it and Enjoy! If your having trouble opening your game, try running it as administrator. If your game crashes, reinstall it in a different file location.
- If you still run into trouble after downloading and installing the game, click here for help.


text:
Hey there, time traveller!
This article was published 13/7/2013 (1502 days ago), so information in it may no longer be current.
Veteran Manitoba Crown attorney Sean Brennan was fired after he dropped charges against a Winnipeg company involved in a workplace accident, only to have the company make a substantial financial donation to a charity he oversees. The story generated some interesting comments.
It would be inappropriate if Brennan was involved in the solicitation of the donation at anytime after he became involved in the prosecution.
The information being released is not sufficient to form an opinion; to keep public confidence in the justice system it is important that justice officials release all the information.
Hopefully Bristol will be able to clarify Brennan's involvement in the solicitation of the donation.
- 23599042
"The provincial government recently notified Sean Brennan he was being dismissed with cause following an investigation into his handling of a file."
Sounds like the government did their homework and connected the dots. They're just not saying yet. One is led to believe its not just a coincidence. Someone had to say, "He told us if we did this, the case would be dropped." Tough to fire a prosecutor.
The government would have to show there was a direct or seriously intimated "this for that." That would be an ethical violation. The ducks are likely in a row.
I assume the WFP is asking for the report.
What's sad is Brennan sounds like a well-motivated guy as he's not seeking a personal benefit. Sounds like he's done great things for the charity.
- bobby b
What a careless and foolish thing to do.
Abuse of power.
- Sameold
The NDP doesn't like its people being involved with charities. In the NDP's mind, all "charity" should be coming from the government. Selinger and his crew can't stand the idea that Manitobans would voluntarily give money to organizations that do good in the community, they believe that only the government should be allowed to be "charitable."
So this guy's out, he didn't do anything wrong, except cross the ideological path of the pathological provincial NDP.
- 23539022
All we have here is some circumstantial evidence that, on the surface, looks bad. But nobody should form any concrete opinions until more information is made available.
- Rodney 2
Brennan should clear the air by filing a grievance or suing for wrongful dismissal. The optics aren't good in terms of the timing of the dropped charges and the donation, but the rationale for dropping the charges should stand or fall on its own merit.
- EBlair1
If the Crown attorney did something wrong, so did Bristol. Hopefully he is not the only one that has to bear the consequences.
- Rockabilly
Like other commenters here, I would like to see more facts about this. At this point, we have reports of two events: a stayed charge and a donation to charity. Whether or not one actually led to the other is the question not yet answered (although certainly implied by the reporter). There are just too many unnamed "sources" being relied upon in this article for me to believe I have an accurate picture of what actually happened.
- Maudoug


text:
"3 day stay in ward 16"
About: Stoke Mandeville Hospital Stoke Mandeville Hospital Aylesbury HP21 8AL
Posted by Anonymous
My experience from first consultation, pre op assessment through to surgical procedure was good. The doctors and nurses were caring and professional at all times. I was treated with respect and dignity at every stage of my treatment. I was considering sending a thank you card to the nursing team but decided to publicly acknowledge my gratitude. I believe we are generally ready to complain but rarely praise so I don't write this review lightly. Thank you so much to everyone in Stoke Mandeville involved in my care.
Response from Anthony Banton, Patient Experience Manager, Buckinghamshire Healthcare NHS Trust 2 years ago
Dear responder
Thank you for your kind words of encouragement. Every month in 2014/15 we receive over 2000 compliments from individuals like yourself and where possible we pass all compliments onto the relevant staff as we know your comments contribute to encouraging our staff to continue to provide a great level of care.
- {{helpful}} of {{total()}} people think this response is helpful
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text:
I Need Some Advise Please! Chocolate Cake Frosting
Baking By cakelove2105 Updated 5 Jan 2014 , 9:03pm by JWinslow
Hello cake lovers,
I would like some advise on what are the best fillings and frosting for a chocolate cake.I would prefer white or at least light-in-color frosting if there's any that match chocolate cakes. Can you also share some recipes?
Thanks a lot
AI'm quite partial to passionfruit with dark chocolate.
I make a raspberry puree with sugar and a little cornstarch added. I think I found the recipe on the Wilton site. Everyone requests this flavor from me.
ARaspberry filling with chocolate cake is our most popular flavour combination.
Raspberry filling with chocolate cake is our most popular flavour combination.
With what frosting or cream do you cover your chocolate cakes? thanks you both :)
AIt depends. If we're covering with paste or leaving it plain with frosting then we use SMBC. If the client wants we'll use a rich, dark chocolate frosting.
I've seen people covering and filling their chocolate cakes with cream cheese frosting, does that taste good? Is that common?
AI use CC filling with carrot cake or pumpkin spice. I don't like it with other flavours.
Taste is never objective.
I have 3 that I get asked to make all the time with chocolate cake. Raspberry, Caramel and Latte. They are all SMBC.


text:
On his always stimulating blog Euangelion, Mike Bird has posted a nice summary of what characterizes both fundamentalists and liberals. These words get thrown around a lot, and Prof. Dr. Bird insightfully clarifies 12 major characteristics of each tendency. Check out Fundamentalist versus Liberal.
Fundamentalists and Liberals: What Characterizes Each?
By JMH on March 17, 2006 in Bible and Theology, History
2 Responses to Fundamentalists and Liberals: What Characterizes Each?
Mike Noakes March 19, 2006 at 7:42 pm #
With the advent of postmodernity (that is, the coming age of postmodernism), Fundies and Liberals seem to be outdated…
Baptist Superman March 22, 2006 at 9:38 pm #
Yes, young man, we are outdated. Now, go witness to someone.
Leave a Reply Click here to cancel reply.
- J. K. Rowling Tells the Truth . . . In Her Fiction July 18, 2017
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- May Women Teach Men at Church? September 2, 2006
- Q & A on Paul and Jesus, Women and the Law January 21, 2007
- Three Objections Enns Makes to Mohler: Apparant Age, Authority, and World-Picture November 4, 2011
- How Often Should a Church Take the Lord's Supper? May 3, 2011


text:
|Publication number
|Publication type
|Application number
|Publication date
|Dec 3, 2002
|Filing date
|Dec 22, 2000
|Priority date
|Dec 23, 1999
|Fee status
|Also published as
|Publication number
|Upvan Narang
|Original Assignee
|Closure Medical Corporation
|Export Citation
|BiBTeX, EndNote, RefMan
|Patent Citations (51), Referenced by (17), Classifications (19), Legal Events (5)
|External Links: USPTO, USPTO Assignment, Espacenet
This application is a continuation-in-part of U.S. patent application Ser. No. 09/471,392, filed Dec. 23, 1999, now U.S. Pat. No. 6,183,593 the entire disclosure of which is incorporated herein by reference.
The invention relates to monomer and polymer adhesive and sealant compositions, and to their production and use for industrial and medical applications.
Monomer and polymer adhesives are used in both industrial (including household) and medical applications. Included among these adhesives are the 1,1-disubstituted ethylene monomers and polymers, such as the α-cyanoacrylates. Since the discovery of the adhesive properties of such monomers and polymers, they have found wide use due to the speed with which they cure, the strength of the resulting bond formed, and their relative ease of use. These characteristics have made the α-cyanoacrylate adhesives the primary choice for numerous applications such as bonding plastics, rubbers, glass, metals, wood, and, more recently, biological tissues.
It is known that monomeric forms of α-cyanoacrylates are extremely reactive, polymerizing rapidly in the presence of even minute amounts of an initiator, including moisture present in the air or on moist surfaces such as animal (including human) tissue. Monomers of α-cyanoacrylates are anionically polymerizable or free radical polymerizable, or polymerizable by zwitterions or ion pairs to form polymers. Once polymerization has been initiated, the cure rate can be very rapid.
Medical applications of 1,1-disubstituted ethylene adhesive compositions include use as an alternate or an adjunct to surgical sutures and/or staples in wound closure, as well as for covering and protecting surface wounds such as lacerations, abrasions, burns, stomatitis, sores, minor cuts and scrapes, and other wounds. When an adhesive is applied to surfaces to be joined, it is usually applied in its monomeric form, and the resultant polymerization gives rise to the desired adhesive bond.
A concern in the use of adhesive compositions for treating wounds is the flexibility and elasticity of the cured adhesive, particularly in the face and body joint areas, such as hands, feet, elbows and knees.
Polymerized cyanoacrylate compositions are in general not flexible. Increased flexibility would improve the utility of cyanoacrylate compositions, particularly in body joint areas. Improved flexibility and elasticity would also make cyanoacrylate compositions better suited to use as drug delivery devices and the like under some circumstances.
Thus, a need exists for improved adhesive compositions, especially for medical uses, wherein the flexibility and elasticity of the adhesive is improved and the performance of the adhesive composition is not compromised. In particular, the need exists for a monomeric adhesive composition that possesses improved flexibility.
Polydimethylsiloxane (or PDMS) is a silicone compound that was developed for use as a dielectric coolant and in solar energy installations. However, it has also been used in other applications.
U.S. Pat. Nos. 4,477,607, 4,533,422 and Re. 32,889, all to Litke, disclose cyanoacrylate compositions that employ fumed silicas treated with polydimethylsiloxane or trialkoxyalkylsilane to improve the thixotropic properties of the compositions. Likewise, U.S. Pat. Nos. 4,764,545 and 4,686,247 to Yosida disclose an adhesive composition comprising an alpha cyanoacrylate and a silica surface-treated respectively with polydimethylsiloxane and with hexamethyldisilazane. Similarly, JP 06-122853 discloses an adhesive composition comprising an alpha cyanoacrylate and a hydrophobic silica surface-treated with dimethyldichlorosilane; U.S. Pat. No. 4,636,539 to Harris et al. discloses an adhesive comprising cyanoacrylate adhesive, fumed silica filler treated with polydialkylsiloxane, and calixarene compound; U.S. Pat. No. 4,180,911 to Bullock discloses a composition and method for use of a cyanoacrylate resin and a silane-treated inorganic powder in direct bonding of an orthodontic bracket structure to teeth and other dental applications; U.S. Pat. No. 4,713,405 to Koga et al. discloses an adhesive composition comprising an alpha cyanoacrylate and a fumed silica having a surface treated with a dimethyldichlorosilane and trialkyl borate; U.S. Pat. No. 5,373,035 to Uemura et al. discloses an adhesive composition comprising an alpha cyanoacrylate and a hydrophobic silica surface-treated with dimethyldichlorosilane; and U.S. Pat. No. 5,248,708 to Uemura et al. discloses an adhesive composition having a particular alpha cyanoacrylate, a fine silica and silanol group.
U.S. Pat. No. 5,214,093 to Nell et al. discloses an adhesive mixture for nonsurgical blepharoplasty. In the main embodiments, the base adhesive component is an oxygen permeable polysiloxane in a solvent. A less preferred embodiment includes a homogeneous mixture of cyanoacrylate adhesive and two separate miscible silicon oil components that are said to provide lubrication and breathability to the skin surface. These components are disclosed to be used in amounts of 50% cyanoacrylate, 25% polydimethylsiloxane and 25% 3-methacryloxy propyltris (trimethoxysiloxy) silane, and can be applied serially or in a mixture. The patent states that the mixture adheres in approximately five minutes and remains somewhat flexible during that time. It provides no further detail about the PDMS other than to indicate that it is "very oily and will penetrate the surface of the tissue to some extent." It is noted that silanes as a general matter raise toxicity issues, although this is not discussed in the Nell patent.
JP 57-70169, JP 57-70171, JP 03-126782, JP 03-296581, JP 04-146982 and JP 06-100838 disclose α-cyanoacrylate adhesive compositions containing specific organosilicon compounds including silicone oils and compounds related to PDMS. However, the disclosed compounds include various side and/or terminal groups that raise issues as to the stability and utility of the resultant compositions.
U.S. Pat. No. 4,906,317 to Liu discloses a cyanoacrylate adhesive composition which employs silacrown compounds as additives.
U.S. Pat. No. 4,837,260 to Sato et al. discloses an adhesive composition comprising an alpha cyanoacrylate and a hydrophobic silica along with particular curing accelerators.
U.S. Pat. No. 4,650,826 to Waniczek et al. discloses the use of silyl ester as a stabilizer for a cyanoacrylate adhesive.
U.S. Pat. No. 5,386,047 to Nakos et al. discloses a polymerizable composition comprising a monomer component, which includes a silicon containing di-alph-cyanopentadienoate disiloxane compound. The monomer component further includes an alpha cyanoacrylate compound.
U.S. Pat. No. 4,705,836 to Ohtsuka et al. discloses a bonding composition including vinyl benzoic acid and cyanoacrylic acid ester. The composition further contains a silane compound.
U.S. Pat. No. 5,140,084 to Mikuni et al. discloses a silicone-containing alph-cyanoacrylate that is useful as an adhesive. Similar silicone-containing alph-cyanoacrylate compositions are also disclosed in JP 04-9388 and JP 04-8780.
The present invention provides a monomeric adhesive composition comprising a polymerizable 1,1-disubstituted ethylene adhesive monomer and a polydimethylsiloxane, which is alkyl, preferably methyl, or phenyl terminated or cyclic. The composition is free or substantially free of silane compounds. Production of the composition includes providing a mixture of the polymerizable monomer and polydimethylsiloxane in a container, and sealing the container, and optionally sterilizing the container and the mixture. The polydimethylsiloxane is preferably selected and provided in an amount such that it is soluble in the monomer at room temperature. The compositions produced, packaged and optionally sterilized according to the present invention are stable, and have extended utility. Compositions of the present invention have increased flexibility, elasticity, tissue (e.g., skin) wettability, stability, moisture vapor transmission rate, oxygen transmission rate, reduced coefficients of friction and/or scar tissue formation and retention avoidance properties. The present invention is thus also directed to methods wherein the composition of the present invention is applied to tissue areas for preventing, reducing or removing scar tissue.
According to the invention, a monomeric adhesive composition comprises at least one polymerizable 1,1-disubstituted ethylene monomer and at least one polydimethylsiloxane (PDMS), and is at least substantially free of silane compounds.
The polydimethylsiloxane suitable for use in the present invention can be alkyl- or phenyl-terminated linear or cyclic or a mixture thereof. Although not limited thereto, the PDMS used in the present invention is preferably a relatively short or small compound, as opposed to a long chain polymer. Thus, for example, the PDMS compound preferably has a low molecular weight, e.g., has a small number of monomer units, and also a low viscosity. The PDMS compound is selected such that it is compatible with the monomer (i.e., does not adversely affect polymerization, cure properties, or shelf-life). Preferably, the polydimethylsiloxane is soluble (i.e., dissolves) in the monomer composition at room temperature (i.e., 20-25� C.) so that it may be combined into the monomer composition without excessive heating of the monomer composition.
Solubility is preferred because a higher elongation effect can be provided by the agent upon polymerization of the adhesive composition when it is dispersed throughout the monomer composition in the form of a solution. In embodiments, the adhesive composition, including the polydimethylsiloxane, can provide an elongation at break of at least 100%, preferably 200-600%, 300-500% or 400-500%, of a polymerized film of the adhesive. If the polydimethylsiloxane is not in the form of a solution, then it is possible that it may settle or otherwise agglomerate, and thereby, upon subsequent polymerization of the composition, not provide the desired consistent elongation effect to the polymerized adhesive composition
Thus, it is preferred in embodiments that the polydimethylsiloxane exhibits an at least substantially uniform concentration throughout the monomer composition. Where excess polydimethylsiloxane is added to the composition, i.e., an amount above the solubility point of the PDMS, it is acceptable that a portion of the PDMS remains undissolved in the composition so long as it does not act as two separate phases. Thus for example, in embodiments a stable microemulsion (with only microphases) may be acceptable.
The amount of polydimethylsiloxane that is added to the monomer composition can depend upon the selection of the specific PDMS and the specific monomer. For example, linear polydimethylsiloxane can often be included in a concentration of about 5-25% by weight, preferably about 5-23% by weight, such as 10-15% by weight, of the adhesive composition relative to the total monomer and polydimethylsiloxane content. Cyclic polydimethylsiloxane can often be included in a concentration of about 5-50% by weight, preferably about 10-30% by weight, such as 10-15, 20 or 25% by weight of the adhesive composition. As noted above, however, contents above these ranges can also be used as desired. The amount of polydimethylsiloxane to be used can be determined by one of ordinary skill in the art using known techniques without undue experimentation in light of the present disclosure.
The polydimethylsiloxane preferably has a low weight average molecular weight. For example, suitable polydimethylsiloxanes preferably have a weight average molecular weight of from about 230 to about 1,500, more preferably from about 300 to about 1,000. Molecular weights outside of these ranges can also be used depending upon the specific polydimethylsiloxane and monomer composition so long as they are soluble or in a microemulsion in the adhesive composition as discussed above.
In exemplary embodiments, a linear polydimethylsiloxane averaging from two to ten, such as two to eight, for example, three, four, five or six monomer units, is preferred. One particularly preferred exemplary linear PDMS is a linear trimethylsiloxy terminated polydimethylsiloxane (TMDS) (CAS #9016-00-6), having a weight average molecular weight of 770, and a viscosity of about 5 centipoise at 25� C.
In other embodiments, the polydimethylsiloxane can be a cyclic polydimethylsiloxane. Such cyclic PDMS compounds are preferably also relatively small, having, for example, from two to ten, such as two to six, for example two to five monomer units. In an exemplary embodiment, a four monomer unit cyclic polydimethylsiloxane can be used. In embodiments, the cyclic PDMS can be selected from octamethylcyclotetrasiloxane (OMTS), decamethylcyclopentasiloxane (DMPS) and dodecamethylcyclohexasiloxane (DMHS). One exemplary cyclic PDMS is a product of United Chemical Technologies Inc. that has the formula C8H24O4Si4 (CAS #556-67-2) having a weight average molecular weight of 296.16, a density of 0.956 at 20� C. and a viscosity of about 2.3 centipoise at 25� C.
The linear PDMS is terminated with alkyl or phenyl groups. The linear or cyclic PDMS can optionally include or be free of alkyl side chain groups. Terminal and side chain groups can include, but are not limited to, alkyl groups with one to twelve, preferably 1-8 such as 1-6 or 1-4, carbon atoms, including for example methyl, ethyl or propyl groups.
Linear PDMS of the invention can be depicted by the formula:
wherein R1 and R2 are independently selected alkyl or phenyl groups. Cyclic PDMS of the invention can be depicted by the formula:
In each case, n is selected to provide the desired molecular weight. Thus n may be, for example, 2 or 3 to 12, preferably 4 to 10 or 4 to 8. One or more of the methyl groups may be alkyl substituted.
The polydimethylsiloxane for use in the present invention preferably has a low viscosity, such as from about 1 to about 15 centipoise at 25� C., as measured by a Brookfield Viscometer. More preferably, the polydimethylsiloxane has a viscosity of from about 2 to about 10 centipoise, such as from about 5 to about 7.5 centipoise at 25� C.
In embodiments, the polydimethylsiloxane is purified prior to mixing with the polymerizable monomer. A polydimethylsiloxane that is at least 98.5% by weight pure (i.e., containing 1.5% by weight or less impurities or ingredients other than polydimethylsiloxane) is preferred. Purification can be achieved, for example, by distillation.
A suitable procedure for selecting a polydimethylsiloxane involves selecting a group of potential polydimethylsiloxanes, assessing their solubility and stability in the monomer composition, and optionally testing for their compatibility with one or more sterilization procedures.
Potential polydimethylsiloxanes for testing can readily be selected by one of ordinary skill in the art from known sources in accordance with the disclosure herein. Once a potential agent is selected, it can be tested for solubility and stability in the monomer composition, such as by mixing an appropriate amount of the polydimethylsiloxane with a desired amount of the monomer composition and any other desired additives.
It is important to maintain the stability of the monomer composition within acceptable levels, such as commercially acceptable levels whereby the composition is not prematurely polymerized prior to application of the monomer composition to a desired substrate. One measure of the stability of the composition, other than a visual examination of the properties of the composition, is a measure of any changes in viscosity of the composition from a time prior to adding the polydimethylsiloxane to a time after adding the polydimethylsiloxane. For example, dramatic increases or decreases in viscosity can indicate instability of the composition, such as premature polymerization or other chemical degradation of the monomer composition or components thereof.
In embodiments of the present invention, it is preferred that the polydimethylsiloxane exhibit stability in the monomer composition for at least five minutes after mixing or dissolving the polydimethylsiloxane in the polymerizable monomer compound. More preferably, stability of the monomer composition is maintained for a time period sufficient to provide a commercially significant shelf-life to the monomer composition, such as 12, 18, or preferably 24 or more months. As used herein, "stability" refers to the composition maintaining a commercially acceptable form for the prescribed amount of time. That is, the composition does not prematurely polymerize or otherwise change form or degrade to the point that the composition is not useful for its intended purpose. Thus, while some polymerization or thickening of the composition may occur, such as can be measured by changes in viscosity of the composition, such change is not so extensive as to destroy or significantly impair the usefulness of the composition.
In embodiments, the adhesive composition has a viscosity of about 1-5000 centipoise, preferably 1-600 centipoise, more preferably 1-100 or 2-50 centipoise such as 2-18, 2-10 or 5-7 centipoise, or 30-500 such as 50-100 or 100-200 centipoise at 25� C. The viscosity can be selected according to the proposed use—e.g., 1-100 centipoise for certain uses and 100-200 centipoise for other uses. Additionally, the composition may be a gel, e.g., 50,000-500,000 centipoise at 25� C. The viscosity of the adhesive composition can be measured with a Brookfield Viscometer. Additionally, in embodiments where a sterilization treatment is applied, the viscosity of the composition should preferably be maintained or increased by a controlled and acceptable amount after sterilization.
Compatibility of the polydimethylsiloxane-containing composition with one or more sterilization procedures is preferred in embodiments of the present invention because many uses of the polymerizable monomer compositions, such as many surgical and other medical applications, require sterilized products. In preferred embodiments, there is substantially no initiation of polymerization of monomeric liquid adhesive compositions that affects the utility of the monomer or monomers caused by the sterilization process.
Sterilization of the monomer composition and/or its packaging can be accomplished by techniques known to the skilled artisan, and is preferably accomplished by methods including, but not limited to, chemical, physical, and/or irradiation methods. Examples of chemical methods include, but are not limited to, exposure to ethylene oxide or hydrogen peroxide vapor. Examples of physical methods include, but are not limited to, sterilization by heat (dry or moist) or retort canning. Examples of irradiation methods include, but are not limited to, gamma irradiation, electron beam irradiation, and microwave irradiation. A preferred method is electron beam irradiation. In embodiments where a composition is to be used for medical applications, the sterilized composition must show low levels of toxicity to living tissue during its useful life.
The monomer (including prepolymeric) adhesive composition may include one or more polymerizable monomers. Preferred monomer compositions of the present invention, and polymers formed therefrom, are useful as tissue adhesives, sealants for preventing bleeding or for covering open wounds, and in other biomedical applications. They find uses in, for example, apposing surgically incised or traumatically lacerated tissues; retarding blood flow from wounds; dressing burns; dressing skin or other superficial or surface wounds such as compromised skin or other tissue (such as abrasions, chaffed or raw skin, minor cuts and scrapes, irritation, sores and/or stomatitis); protecting intact skin; and aiding repair and regrowth of living tissue. They are particularly useful for treating tissues that are subjected to flexing, such as faces and joints such as on hands, feet, elbows and knees. Monomer compositions of the present invention, and polymers formed therefrom, are also useful in industrial and home applications, for example in bonding rubbers, plastics, wood, composites, fabrics, and other natural and synthetic materials, particularly when applied at an area that is subjected to flexing.
Preferred monomers that may be used in this invention are readily polymerizable, e.g. anionically polymerizable or free radical polymerizable, or polymerizable by zwitterions or ion pairs to form polymers. Such monomers include those that form polymers, that may, but do not need to, biodegrade. Such monomers are disclosed in, for example, U.S. Pat. No. 5,328,687 to Leung, et al., which is hereby incorporated in its entirety by reference herein.
Useful 1,1-disubstituted ethylene monomers include, but are not limited to, monomers of the formula:
wherein X and Y are each strong electron withdrawing groups, and R is H, —CH═CH2 or, provided that X and Y are both cyano groups, a C1-C4 alkyl group.
Examples of monomers within the scope of formula (I) include α-cyanoacrylates, vinylidene cyanides, C1-C4 alkyl homologues of vinylidene cyanides, dialkyl methylene malonates, acylacrylonitriles, vinyl sulfinates and vinyl sulfonates of the formula CH2═CX′Y′ wherein X′ is —SO2R′ or —SO3R′ and Y′ is —CN, —COOR′, —COCH3, —SO2R′ or —SO3R′, and R′ is H or hydrocarbyl.
Preferred monomers of formula (I) for use in this invention are α-cyanoacrylates. These monomers are known in the art and have the formula
wherein R2 is hydrogen and R3 is a hydrocarbyl or substituted hydrocarbyl group; a group having the formula —R4—O—R5—O—R6 or —R5—O—R6, wherein R4 is a 1,2-alkylene group having 2-4 carbon atoms, R5 is an alkylene group having 2-4 carbon atoms, and R6 is an alkyl group having 1-6 carbon atoms; or a group having the formula
wherein R7 is
wherein n is 1-10, preferably 1-5, and R8 is an organic moiety.
Examples of suitable hydrocarbyl and substituted hydrocarbyl groups include straight chain or branched chain alkyl groups having 1-16 carbon atoms; straight chain or branched chain C1-C16 alkyl groups substituted with an acyloxy group, a haloalkyl group, an alkoxy group, a halogen atom, a cyano group, or a haloalkyl group; straight chain or branched chain alkenyl groups having 2 to 16 carbon atoms; straight chain or branched chain alkynyl groups having 2 to 12 carbon atoms; cycloalkyl groups; aralkyl groups; alkylaryl groups; and aryl groups.
The organic moiety R8 may be substituted or unsubstituted and may be straight chain, branched or cyclic, saturated, unsaturated or aromatic. Examples of such organic moieties include C1-C8 alkyl moieties, C2-C8 alkenyl moieties, C2-C8 alkynyl moieties, C3-C12, cycloaliphatic moieties, aryl moieties such as phenyl and substituted phenyl and aralkyl moieties such as benzyl, methylbenzyl, and phenylethyl. Other organic moieties include substituted hydrocarbon moieties, such as halo (e.g., chloro-, fluoro- and bromo-substituted hydrocarbons) and oxy-substituted hydrocarbon (e.g., alkoxy substituted hydrocarbons) moieties. Preferred organic radicals are alkyl, alkenyl, and alkynyl moieties having from 1 to about 8 carbon atoms, and halo-substituted derivatives thereof. Particularly preferred are alkyl moieties of 4 to 6 carbon atoms.
In the cyanoacrylate monomer of formula (II), R3 is preferably an alkyl group having 1-10 carbon atoms or a group having the formula —AOR9, wherein A is a divalent straight or branched chain alkylene or oxyalkylene moiety having 2-8 carbon atoms, and R9 is a straight or branched alkyl moiety having 1-8 carbon atoms.
Examples of groups represented by the formula —AOR9 include 1-methoxy-2-propyl, 2-butoxy ethyl, isopropoxy ethyl, 2-methoxy ethyl, and 2-ethoxy ethyl.
The α-cyanoacrylates of formula (II) can be prepared according to methods known in the art. U.S. Pat. Nos. 2,721,858 and 3,254,111, each of which is hereby incorporated in its entirety by reference, disclose methods for preparing α-cyanoacrylates. For example, the α-cyanoacrylates can be prepared by reacting an alkyl cyanoacetate with formaldehyde in a non-aqueous organic solvent and in the presence of a basic catalyst, followed by pyrolysis of the anhydrous intermediate polymer in the presence of a polymerization inhibitor. The α-cyanoacrylate monomers prepared with low moisture content and essentially free of impurities are preferred for biomedical use.
The α-cyanoacrylates of formula (II) wherein R3 is a group having the formula R4—O—R5—O—R6 or —R5—O—R6 can be prepared according to the method disclosed in U.S. Pat. No. 4,364,876 to Kimura et al., which is hereby incorporated in its entirety by reference. In the Kimura et al. method, the α-cyanoacrylates are prepared by producing a cyanoacetate by esterifying cyanoacetic acid with an alcohol or by transesterifying an alkyl cyanoacetate and an alcohol; condensing the cyanoacetate and formaldehyde or para-formaldehyde in the presence of a catalyst at a molar ratio of 0.5-1.5:1, preferably 0.8-1.2:1, to obtain a condensate; depolymerizing the condensation reaction mixture either directly or after removal of the condensation catalyst to yield crude cyanoacrylate; and distilling the crude cyanoacrylate to form a high purity cyanoacrylate.
The α-cyanoacrylates of formula (II) wherein R3 is a group having the formula
can be prepared according to the procedure described in U.S. Pat. No. 3,995,641 to Kronenthal et al., which is hereby incorporated in its entirety by reference. In the Kronenthal et al. method, such α-cyanoacrylate monomers are prepared by reacting an alkyl ester of an α-cyanoacrylic acid with a cyclic 1,3-diene to form a Diels-Alder adduct which is then subjected to alkaline hydrolysis followed by acidification to form the corresponding α-cyanoacrylic acid adduct. The α-cyanoacrylic acid adduct is preferably esterified by an alkyl bromoacetate to yield the corresponding carbalkoxymethyl α-cyanoacrylate adduct. Alternatively, the α-cyanoacrylic acid adduct may be converted to the α-cyanoacrylyl halide adduct by reaction with thionyl chloride. The α-cyanoacrylyl halide adduct is then reacted with an alkyl hydroxyacetate or a methyl substituted alkyl hydroxyacetate to yield the corresponding carbalkoxymethyl α-cyanoacrylate adduct or carbalkoxy alkyl α-cyanoacrylate adduct, respectively. The cyclic 1,3-diene blocking group is finally removed and the carbalkoxy methyl α-cyanoacrylate adduct or the carbalkoxy alkyl α-cyanoacrylate adduct is converted into the corresponding carbalkoxy alkyl α-cyanoacrylate by heating the adduct in the presence of a slight deficit of maleic anhydride.
Examples of monomers of formula (I) include cyanopentadienoates and (α-cyanoacrylates of the formula:
wherein Z is —CH═CH2 and R3 is as defined above. The monomers of formula (III) wherein R3 is an alkyl group of 1-10 carbon atoms, i.e., the 2-cyanopenta-2,4-dienoic acid esters, can be prepared by reacting an appropriate 2-cyanoacetate with acrolein in the presence of a catalyst such as zinc chloride. This method of preparing 2-cyanopenta-2,4-dienoic acid esters is disclosed, for example, in U.S. Pat. No. 3,554,990, which is hereby incorporated in its entirety by reference.
Preferred α-cyanoacrylate monomers used in this invention are alkyl α-cyanoacrylates including octyl cyanoacrylate, such as 2-octyl cyanoacrylate; dodecyl cyanoacrylate; 2-ethylhexyl cyanoacrylate; butyl cyanoacrylate such as n-butyl, iso-butyl or tert-butyl cyanoacrylate; ethyl cyanoacrylate; methyl cyanoacrylate; 3-methoxybutyl cyanoacrylate; 2-butoxyethyl cyanoacrylate; 2-isopropoxyethyl cyanoacrylate; and 1-methoxy-2-propyl cyanoacrylate. More preferred monomers are n-butyl and 2-octyl α-cyanoacrylate. Monomers utilized for medical purposes in the present application should be very pure and contain few impurities (e.g., surgical grade). Monomers utilized for industrial purposes need not be as pure.
The composition may optionally also include at least one other plasticizing agent that assists in imparting flexibility to the polymer formed from the monomer. The plasticizing agent preferably contains little or no moisture and should not significantly affect the stability or polymerization of the monomer.
Examples of suitable plasticizers include tributyl citrate, acetyl tri-n-butyl citrate (ATBC), dimethyl sebacate, triethyl phosphate, tri(2-ethylhexyl)phosphate, tri(p-cresyl)phosphate, glyceryl triacetate, glyceryl tributyrate, diethyl sebacate, dioctyl adipate, isopropyl myristate, butyl stearate, lauric acid, trioctyl trimellitate, dioctyl glutarate, and mixtures thereof. Preferred plasticizers are tributyl citrate and acetyl tributyl citrate. In embodiments, suitable plasticizers include polymeric plasticizers, such as polyethylene glycol (PEG) esters and capped PEG esters or ethers, polyester glutarates and polyester adipates. Some thickeners, such as poly-2-ethylhexylcyanoacrylate, can also impart flexibility to the polymer. Polymethyl methacrylate (PMMA) and hexadimethylsilazane (HDMS) are particularly useful as plasticizers in high viscosity (e.g., greater than 100 centipoise at 25� C.) formulations containing PDMS, while tributyl citrate and acetyl tributyl citrate are particularly useful as plasticizers in low viscosity (e.g., less than 50 centipoise at 25� C.) formulations containing PDMS.
The addition of other plasticizing agents, in addition to the polydimethylsiloxane, in amounts ranging from about 0.5 wt. % to about 25 wt. %, or from about 1 wt.% to about 20 wt .%, or from about 3 wt. % to about 15 wt. % or from about 4 wt. % to about 6 wt. %, based on the entire composition, may further increase elongation and toughness of the polymerized monomer over polymerized monomers not having the additional plasticizing agents.
The composition may also optionally include at least one thixotropic agent. Suitable thixotropic agents are known to the skilled artisan and include, but are not limited to, silica gels such as those treated with a silyl isocyanate, and optionally surface treated titanium dioxide. However, in some embodiments, the adhesive composition contains no, or substantially no, silica. Examples of suitable thixotropic agents and thickeners are disclosed in, for example, U.S. Pat. No. 4,720,513, and U.S. patent application Ser. No. 09/374,207 filed Aug. 12, 1999, the entire disclosures of which are hereby incorporated in their entirety.
The thickening agents may be selected from among known thickeners, including, but not limited to, poly(2-ethylhexyl methacrylate), poly(2-ethylhexyl acrylate) and celluose acetate butyrate. Suitable thickeners include, for example, polycyanoacrylates, polyoxalates, lactic-glycolic acid copolymers, polycaprolactone, lactic acid-caprolactone copolymers, poly(caprolactone+DL-lactide+glycolide), polyorthoesters, polyalkyl acrylates, copolymers of alkylacrylate and vinyl acetate, polyalkyl methacrylates, and copolymers of alkyl methacrylates and butadiene. Examples of alkyl methacrylates and acrylates are poly(butylmethacrylate) and poly(butylacrylate), also copolymers of various acrylate and methacrylate monomers, such as poly(butylmethacrylate-co-methylmethacrylate). Biodegradable polymer thickeners are preferred for some uses such as some surgical uses. Preferably, the thickening agent is soluble in a monomer composition at room temperature (i.e., 20-25� C.) so that it may be added to the monomer composition without excessive heating of the monomer composition and remain uniformly combined in the composition.
The composition may also optionally include at least one natural or synthetic rubber to impart impact resistance, which is preferable especially for industrial compositions of the present invention. Suitable rubbers are known to the skilled artisan. Such rubbers include, but are not limited to, dienes, styrenes, acrylonitriles, and mixtures thereof. Examples of suitable rubbers are disclosed in, for example, U.S. Pat. Nos. 4,313,865 and 4,560,723, the disclosures of which are hereby incorporated in their entireties.
The composition may also optionally include one or more stabilizers, preferably both at least one anionic vapor phase stabilizer and at least one anionic liquid phase stabilizer. These stabilizing agents inhibit premature polymerization. Such stabilizing agents may also include mixtures of anionic stabilizing agents and radical stabilizing agents such as hydroquinone, p-methoxyphenol and butylated hydroxy-anisole (BHA). Any mixture of stabilizers is included as long as the mixture does not inhibit the desired polymerization of the monomer.
The anionic vapor phase stabilizers may be selected from among known stabilizers, including, but not limited to, sulfur dioxide, boron trifluoride, and hydrogen fluoride. The amount of anionic vapor phase stabilizer that is added to the monomer composition depends on the identity of the liquid phase stabilizer(s) chosen in combination with it, the monomer to be stabilized, as well as the packaging material to be used for the composition. Preferably, each anionic vapor phase stabilizer is added to give a concentration of less than 200 parts per million (ppm). In preferred embodiments, each anionic vapor phase stabilizer is present from about 1 to 200 ppm, more preferably from about 10 to 75 ppm, even more preferably from about 10 to 50 ppm, and most preferably from 10 to 20 ppm. The amount to be used can be determined by one of ordinary skill in the art using known techniques without undue experimentation.
In embodiments, the vapor phase comprises, among other things, an anionic stabilizer that is sulfur dioxide. In embodiments, the vapor phase comprises, among other things, a stabilizer that is boron trifluoride or hydrogen fluoride. A combination of sulfur dioxide and boron trifluoride or hydrogen fluoride is preferable in some embodiments.
In embodiments, the liquid phase anionic stabilizer is a very strong acid. As used herein, a very strong acid is an acid that has an aqueous pKa of less than 1.0. Suitable very strong acidic stabilizing agents include, but are not limited to, very strong mineral and/or oxygenated acids. Examples of such very strong acids include, but are not limited to, sulfuric acid (pKa −3.0), perchloric acid (pKa −5), hydrochloric acid (pKa −7.0), hydrobromic acid (pKa −9), fluorosulfonic acid (pKa <−10), chlorosulfonic acid (pka−10). In embodiments, the very strong acid liquid phase anionic stabilizer is added to give a final concentration of 1 to 200 ppm. Preferably, the very strong acid liquid phase anionic stabilizer is present in a concentration of from about 5 to 80 ppm, more preferably 10 to 40 ppm. The amount of very strong acid liquid phase anionic stabilizer to be used can be determined by one of ordinary skill in the art without undue experimentation.
Preferably, the very strong acid liquid phase anionic stabilizer is sulfuric acid, perchloric acid, or chlorosulfonic acid. More preferably, the very strong acid liquid phase anionic stabilizer is sulfuric acid.
In embodiments, sulfur dioxide is used as a vapor phase anionic stabilizer and sulfuric acid is used as a liquid phase anionic stabilizer.
The composition may also optionally include at least one other anionic stabilizing agent that inhibits premature polymerization. These agents are herein referred to as secondary anionic active agents to contrast them with the strong or very strong liquid phase anionic stabilizers, which are referred to hereinbelow as "primary" anionic stabilizers. The secondary anionic active agents can be included in the compositions to adjust the cure speed of the adhesive composition, for example.
The secondary anionic active agent would normally be an acid with a higher pKa than the primary anionic stabilizing agent and may be provided to more precisely control the cure speed and stability of the adhesive, as well as the molecular weight of the cured adhesive. Any mixture of primary anionic stabilizers and secondary active agents is included as long as the chemistry of the composition is not compromised and the mixture does not significantly inhibit the desired polymerization of the composition. Furthermore, the mixture should not, in medical adhesive compositions, show unacceptable levels of toxicity.
Suitable secondary anionic active agents include those having aqueous pKa ionization constants ranging from 2 to 8, preferably from 2 to 6, and most preferably from 2 to 5. Examples of such suitable secondary anionic stabilizing agents include, but are not limited to, phosphoric acid (pka2.2), organic acids, such as acetic acid (pKa4.8), benzoic acid (pka4.2), chloroacetic acid (pka2.9), cyanoacetic acid, and mixtures thereof. Preferably these secondary anionic stabilizing agents are organic acids, such as acetic acid or benzoic acid. In embodiments, the amount of acetic acid and/or benzoic acid is about 25-500 ppm. The concentration of acetic acid is typically 50-400 ppm, preferably 75-300 ppm, and more preferably 100-200 ppm. When using a stronger acid such as phosphoric acid, a concentration of 20-100 ppm, preferably 30-80 ppm, and more preferably 40-60 ppm may be utilized.
Combinations of at least one vapor phase stabilizer and at least one liquid phase anionic stabilizer are preferred. For example, combinations of sulfur dioxide and sulfuric acid; sulfur dioxide and perchloric acid; sulfur dioxide and chlorosulfonic acid; boron trifluoride and sulfuric acid; boron trifluoride and perchloric acid; boron trifluoride and chlorosulfonic acid; boron trifluoride and methanesulfonic acid; hydrogen fluoride and sulfuric acid; hydrogen fluoride and perchloric acid; hydrogen fluoride and chlorosulfonic acid; hydrogen fluoride and methanesulfonic acid; boron trifluoride, sulfur dioxide, and sulfuric acid; sulfur dioxide, sulfuric acid and acetic acid; and other combinations can be used. The two types of anionic stabilizers are chosen in conjunction such that the stabilizers are compatible with the chosen adhesive composition and each other, as well as with the packaging material and the equipment used to make and package the composition. In other words, the combination of vapor phase stabilizer(s), liquid phase stabilizer(s), radical stabilizers and monomer should be such that a stabilized, substantially unpolymerized adhesive composition is present after packaging.
It has been found, however, that compositions of the invention can require less stabilizer than corresponding compositions without the PDMS.
The stability, and thus the shelf-life, of some monomeric adhesive compositions can be further enhanced and extended through careful regulation of the packaging. Treated (e.g., fluorinated polymer) packaging such as that disclosed in copending U.S. patent application Ser. No. 09/430,289 filed Oct. 29, 1999, which is hereby incorporated by reference in its entirety, is preferred and may reduce the amount of stabilizer that is combined into the composition.
The compositions may also include pH modifiers to control the rate of degradation of the resulting polymer, as disclosed in U.S. patent application Ser. No. 08/714,288, filed Sep. 18, 1996, the entire disclosure of which is hereby incorporated by reference.
Medical compositions of the present invention may also include at least one biocompatible agent effective to reduce active formaldehyde concentration levels produced during in vivo biodegradation of the polymer (also referred to herein as "formaldehyde concentration reducing agents"). Preferably, this component is a formaldehyde scavenger compound. Examples of formaldehyde scavenger compounds useful in this invention include sulfites; bisulfites; mixtures of sulfites and bisulfites; ammonium sulfite salts; amines; amides; imides; nitrites; carbamates; alcohols; mercaptans; proteins; mixtures of amines, amides, and proteins; active methylene compounds such as cyclic ketones and compounds having a b-dicarbonyl group; and heterocyclic ring compounds free of a carbonyl group and containing an NH group, with the ring made up of nitrogen or carbon atoms, the ring being unsaturated or, when fused to a phenyl group, being unsaturated or saturated, and the NH group being bonded to a carbon or a nitrogen atom, which atom is directly bonded by a double bond to another carbon or nitrogen atom. Additional examples of formaldehyde scavenger compounds useful in this invention and methods for their implementation can be found in U.S. Pat. Nos. 5,328,687, 5,514,371, 5,514,372, 5,575,997, 5,582,834 and 5,624,669, all to Leung et al., which are hereby incorporated by reference in their entireties.
To improve the cohesive strength of adhesives formed from the compositions of this invention, difunctional monomeric cross-ling agents may be added to the monomer compositions of this invention. Such crosslinking agents are known. U.S. Pat. No. 3,940,362 to Overhults, which is hereby incorporated in its entirety by reference, discloses such cross-linking agents. Examples of suitable crosslinking agents include alkyl bis(2-cyanoacrylates), triallyl isocyanurates, alkylene diacrylates, alkylene dimethacrylates, trimethylol propane triacrylate, and alkyl bis(2-cyanoacrylates). A catalytic amount of an amine activated free radical initiator or rate modifier may be added to initiate polymerization or to modify the rate of polymerization of the cyanoacrylate monomer/crosslinking agent blend.
In embodiments of the present invention, the composition and/or its applicator may contain materials such as a polymerization initiator, accelerator, rate-modifier, flavorant, and/or cross-linking agent for initiating polymerization and/or cross-linking of the polymerizable monomer material. Suitable materials and applicators and packaging systems are disclosed in U.S. Pat. No. 5,928,611 and U.S. patent applications Ser. Nos. 09/430,177, 09/430,176, 09/430,289, 09/430,290, and 09/430,180 filed Oct. 29, 1999; 09/343,914 filed Jun. 30, 1999; 09/385,030 filed Aug. 30, 1999; Ser. No. and 09/176,889 filed Oct. 22, 1998; the entire disclosures of which are incorporated herein by reference. A preferred initiator for some uses, especially industrial uses, is dimethyl toluidine.
The compositions of this invention may further contain fibrous reinforcement and colorants such as dyes, pigments, and pigment dyes. Examples of suitable fibrous reinforcement include PGA microfibrils, collagen microfibrils, cellulosic microfibrils, and olefinic microfibrils. Examples of suitable colorants include 1-hydroxy-4-[4-methylphenyl-amino]-9,10 anthracenedione (D+C violet No. 2); disodium salt of 6-hydroxy-5-[(4-sulfophenyl)axo]-2-naphthalene-sulfonic acid (FD+C Yellow No. 6); 9-(o-carboxyphenoyl)-6-hydroxy-2,4,5,7-tetraiodo-3H-xanthen-3-one, disodium salt, monohydrate (FD+C Red No. 3); 2-(1,3-dihydro-3-oxo-5-sulfo-2H-indol-2-ylidene)-2,3-dihydro-3-oxo-1H-indole-5-sulfonic acid disodium salt (FD+C Blue No. 2); and [phthalocyaninato (2-)]copper.
The compositions of this invention may further contain preservatives. In embodiments, the preservatives may be selected from among known preservatives including, but not limited to, parabens and cresols. For example, suitable parabens include, but are not limited to, alkyl parabens and salts thereof, such as methylparaben, methylparaben sodium, ethylparaben, propylparaben, propylparaben sodium, butylparaben, and the like. Suitable cresols include, but are not limited to, cresol, chlorocresol, and the like. The preservatives can also be selected from other known agents including, but not limited to, hydroquinone, pyrocatechol, resorcinol, 4-n-hexyl resorcinol, captan (i.e., 3a,4,7,7a-tetrahydro-2-((trichloromethyl)thio)-1H-isoindole-1,3(2H)-dione), methyl-4-hydroxybenzoate, benzalkonium chloride, benzalkonium chloride solution, benzethonium chloride, benzoic acid, benyzl alcohol, butylated hydroxy-anisole (BHA), cetylpyridinium chloride, chlorobutanol, dehydroacetic acid, o-phenylphenol, phenol, phenylethyl alcohol, potassium benzoate, potassium sorbate, sodium benzoate, sodium dehydroacetate, sodium propionate, sorbic acid, thimerosal, thymol, phenylmercuric compounds such as phenylmercuric borate, phenylmercuric nitrate and phenylmercuric acetate, formaldehyde, and formaldehyde generators such as the preservatives Germall II� and Germall 115� (imidazolidinyl urea, available from Sutton Laboratories, Charthan, N.J.). In embodiments, mixtures of two or more preservatives can also be used. See also U.S. patent application Ser. No. 09/430,180 filed Oct. 29, 1999, which is hereby incorporated herein in its entirety by reference.
The present invention is also directed to the use of compositions, including above-described compositions, to remove, prevent or reduce scar tissue. It has surprisingly been found that compositions including PDMS, including but not limited to the above-described PDMS-containing compositions, can be applied to tissue for the purpose and effect of reducing, or even eliminating, scar tissue. In a similar manner, such compositions can also be applied to tissue surfaces for the prevention of scar tissue formation. Although the composition to be applied is preferably the above-described PDMS-containing adhesive composition, any suitable PDMS-containing adhesive composition can be used, without the PDMS compound necessarily being limited to those described in detail above.
Exemplary embodiments of the present invention for the removal, prevention or reduction of scar tissue can include various methods wherein the composition is applied to tissue areas, such as skin areas, where scar tissue is already present or where scar tissue is prone, or likely, to form. In such methods, the composition can be applied by itself or in combination with other topical compositions and/or medications to aid in the removal, prevention or reduction of scar tissue.
In an exemplary embodiment, a method for removing or reducing scar tissue already present can include applying the composition in an amount sufficient to cover a skin area where scar tissue is present. The method can also include a step of covering the applied composition with a protective bandage or other adhesive composition to protect the applied composition from frictional contact with, for example, clothing. The application of the composition of the present invention can be repeated until the scar tissue is substantially removed or reduced.
According to embodiments of the present invention, the presence and/or appearance of scar tissue can be partially, substantially, or even completely removed. For example, treatment of scar tissue using compositions of the present invention can result, for example, in a reduction of scar tissue, such as measured in area, in an amount of at least about 20% or more. In embodiments, the scar tissue reduction can be in an amount of at least about 30% or about 40% or more, and preferably is at least about 50% or more. In terms of scar tissue reduction, substantial reductions of at least about 80% or more or at least about 85% or 90% or more are preferred. In embodiments, complete reduction of 100% of the scar tissue may be realized.
Although not limited by any particular theory, it is believed that the PDMS-containing composition actually reduces the presence of scar tissue. However, regardless of the actual mechanism, a reduction in at least the appearance of the scar tissue occurs. Thus, whether the scar tissue itself is reduced, or if only its appearance is reduced such as by overgrowth of healthy tissue, the scar itself is reduced and/or eliminated.
Similarly, in an exemplary embodiment, a method of the present invention for preventing scar tissue formation can include applying an amount of the above-described composition to a tissue area wherein scar tissue may be prone, or likely, to form. Preferably, the amount of composition applied is sufficient to cover the entire tissue area and optionally a surrounding tissue area so that scar tissue formation is sufficiently prevented. Tissue areas where scar tissue may be prone, or likely, to form can include skin areas where a wound has been inflicted including, but not limited to, skin areas that are prone, or likely, to suffer from cuts, abrasions, burns, etc. These injuries can be injuries that result from medical treatment, including, for example, surgery, as well as injuries that occur in every day life. In methods of the present invention for preventing scar tissue formation, the composition is applied to the tissue, or skin, area either prior to an injury ,or wound, when the area of tissue is uncompromised or immediately after the occurrence of an injury, or wound. For instance, the composition can be applied to a skin area that one believes will suffer an injury before the injury occurs, or the composition can be applied to a skin area immediately after the injury occurs. If applied to the skin area after the injury has occurred, the applied composition may or may not be covered with a protective bandage and/or adhesive composition to prevent the composition from being removed due to frictional contact with clothing or other objects.
The present invention is also directed to a cosmetic agent comprising the above-described composition for removing, reducing or preventing scar tissue. Such an agent may comprise one or more additional components and/or medicaments together with the above-described composition to assist in the removal, reduction or prevention of scar tissue.
Furthermore, the present invention is also directed to the use of the above composition for obtaining a cosmetic agent for removing, reducing or preventing scar tissue. The use of the above described composition for obtaining such a cosmetic agent encompasses the preparation and combination of the above composition with other materials and/or medicaments during manufacturing to obtain a cosmetic agent for scar tissue removal, reduction or prevention.
In addition to the above PDMS-containing compositions, the composition of the present invention can also include other siloxane or PDMS-containing materials to prevent, reduce or remove scar tissue. For example, in exemplary embodiments of the present invention the composition may include additional scar reduction agents including, but not limited to siloxane-containing monomers, siloxane-containing polymers, fluorinated siloxanes, and siloxanes.
Examples of suitable siloxane-containing monomers and siloxane-containing polymers include, but are not limited to, siloxane-containing 1,1-disubstituted ethylene monomers. Particularly preferred suitable siloxane-containing monomers and polymers include, but are not limited to, siloxane-containing α-cyanoacrylates such as alkyl α-cyanoacrylates having an alkyl chain length of from about 1 to about 20 carbon atoms, preferably from about 2 to about 12 carbon atoms. Examples of such siloxane-containing alkyl α-cyanoacrylates include, for example, siloxane-containing ethyl, butyl, and octyl α-cyanoacrylates. Other particularly preferred suitable siloxane-containing monomers and polymers include, for example, siloxane-containing cyanopentadienoates.
Preferably, where siloxane-containing cyanopentadienoates are used, it is preferred, although not required, that the compound not be a di-α-cyanopentadienoate disiloxane of the formula:
wherein R is —CH═CH— or —C(═CH2)— and R″ are the same or different hydrocarbon or halosubstituted hydrocarbon groups, as disclosed in U.S. Pat. No. 5,386,047 to Nakos et al., the entire disclosure of which is incorporated herein by reference. However, when such compounds are used as anti-scar agents, they are preferably used in the composition in combination with non-siloxane containing polymerizable adhesive monomers.
Suitable siloxane groups incorporated into the monomer or polymer include, but are not limited to, disiloxane having the formula —SiH2—O—SiH3, trisiloxane such as linear trisiloxane having the formula —(SiH2—O)2—SiH3 or branched trisiloxane having the formula —SiH(—O—SiH3) 2, or linear or branched longer siloxane units such as those having the formulas —(SiH2—O)n—SiH3, —(Si(CH3)2—O)n—SiH3, —(Si(CH3)2—O)n—Si(CH3)3, or —SiH(—O—Si H3)n(—O—SiH3)m, where n and m are integers of any suitable number to provide a desired molecular weight of the monomer. For example, n and m can independently be an integer of from about 1 to about 100, preferably from about 1 to about 50.
Thus, for example, examples of suitable siloxane-containing α-cyanoacrylates include, but are not limited to, monomers of the formula:
wherein R is a siloxane-containing group of the formula —(O—Si(CH3)2)n—O—Si(CH3)3, where n is from about 1 to about 100, preferably from about 1 to about 50.
Polymers of the above monomeric units may also be included in the adhesive composition, in embodiments. Thus, for example, poly(siloxane-containing cyanoacrylate) can be used as an anti-scar agent. Thus, for example, a poly(siloxane-cyanoacrylate of the following formula can be used:
where m represents the number of repeating units in the polymer and n is from about 1 to about 100, preferably from about 1 to about 50. Where the siloxane-containing polymer is added to the adhesive composition as a separate component, the polymer is preferably a low molecular weight polymer in which m ranges, for example, from about 2 to about 2000 or more, preferably from about 2 to about 1000 or from about 500 to about 1800, more preferably from about 100 to about 500 or from about 1000 to about 1700.
Other examples of suitable siloxane containing polymers include, but are not limited to, siloxane-containing copolyols, such as copolymers of siloxane and polyethylene glycol. Particularly suitable copolyols include dimethicone copolyol, also referred to as polydimethylsiloxane polyethylene glycol.
The dimethicone copolyol suitable for use in the present invention can include a polydimethylsiloxane (PDMS) segment that can be alkyl- or phenyl-terminated linear or cyclic or a mixture thereof. Although not limited thereto, the PDMS segment of the dimethicone copolyol used in the present invention is preferably a relatively short or small compound, as opposed to a long chain polymer. Thus, for example, the PDMS segment preferably has a low molecular weight, e.g., has a small number of monomer units, and also a low viscosity. Preferably, in embodiments, the PDMS segment is a linear compound, rather than a cyclic compound.
Still other examples of suitable siloxane containing polymers include, but are not limited to, the MASIL� series of products available from BASF Corporation and the SILWET� series of products available from Union Carbide.
When the scar prevention, reduction or removal agent is a fluorinated monomer or a siloxane-containing monomer, it is preferred that the monomer be polymerizable with the polymerizable adhesive monomer contained in the adhesive composition. In this embodiment, the agent will thus become an integral part of the polymer film during polymerization. However, in other embodiments, the fluorinated monomer or siloxane-containing monomer need not be polymerizable with the polymerizable adhesive monomer, and can thus exist as a separate species in the resultant polymer film.
When the agent is a fluorinated monomer or polymer or a siloxane-containing monomer or polymer, or even any of the other agents described herein, it is preferred that the agent be soluble both in the polymerizable monomer of the adhesive composition, as well as in the polymer formed therefrom. However, in embodiments, it may be acceptable for the agent to be insoluble in one or both of the polymerizable monomer of the adhesive composition, and the polymer formed therefrom
Furthermore, in the case of the siloxane-containing monomer or polymer, it is preferred, although not required, that the compound not be a siloxane compound having a 2-cyanoacryloyl group at each end. Instead, in such cases, the compound preferable does not include any 2-cyanoacryloyl groups, although the compound may have a 2-cyanoacryloyl group at one end, but other end of the compound is preferably terminated by a different group. However, where such siloxane compounds having a2-cyanoacryloyl group at each end are used as agents in embodiments of the present invention, it is preferred that the compounds be used in amounts of less than 1 weight percent, or more than 50 weight percent, based on the total composition.
Various fluorinated siloxanes can also be used as anti-scar agents in the compositions of the present invention. By fluorinated siloxanes is meant a compound containing silicon, oxygen and fluorine atoms, where the silicon atoms are bonded either to a fluorine atom or an oxygen atom. Additionally, the fluorinated siloxanes can also include hydrogen atoms, where a hydrogen atom is bonded to a silicon atom in place of a fluorine or oxygen atom.
According to embodiments of the present invention, suitable fluorinated siloxanes includes those having a weight average molecular weight of from about 200 to about 20,000, and/or those having a viscosity, as measured at 25� C., of from about 100 to about 100,000 cP. However, fluorinated siloxanes having molecular weights and/or viscosities outside of these ranges can also be used.
Suitable fluorinated siloxanes include, for example, the fluoropropyl fluids FF157, 150-10M and F160 as well as similar products, available from GE (Waterford, New York); the MED series of products, such as MED-400, MED-420 and MED-460 and similar products, available from NuSil (Carpinteria, Calif.); and the PS series of products, such as PS 181, PS 182, PS 1836, PS 184.5, and PS 187 and similar products available from UCT (Bistol, Penn.). The MED-400 product is identified as a 100% fluorinated siloxane; the MED-420 product is identified as a copolymer of fluorosiloxane and polydimethylsiloxane, of which about 20 mol% is fluorosiloxane; and the MED-460 product is identified as a copolymer of fluorosiloxane and polydimethylsiloxane, of which about 60 mol% is fluorosiloxane.
Suitable fluorinated siloxanes include, but are in no way limited to, fluroinated siloxanes such as polymethyl-3,3,3-trifluoropropyl siloxane of the formula:
where n represents the number of repeating units and can range, for example, from about 1 to about 2000, preferably from about 2 or 10 to about 1500 or 1900, such as from about 2 to about 50 or about 100, or from about 500 or about 1000 to about 1500 or about 1800.
Likewise, siloxanes in and of themselves are also suitable for use as the anti-scar agent in the present invention. Thus, for example, suitable siloxanes such as octyl siloxane and octadecyl siloxane can be used. Octyl siloxane and octadecyl siloxane have the following formula:
where m is 7 for octyl siloxane or 17 for octadecyl siloxane, and n represents the number of repeating units and can range, for example, from about 1 to about 2000, preferably from about 2 or 10 to about 1500 or 1900, such as from about 2 to about 50 or about 100, or from about 500 or about 1000 to about 1500 or about 1800.
In embodiments of the present invention where siloxanes are used as the anti-scar agent, it is also preferred, although not required, that the siloxane be used as a separate component in the composition, and not be added to the composition in the form of a surface treatment agent on silica or similar particles. It is also preferred, although not required, that the siloxane not have any hydrogensilyl groups. Thus, for example, it is preferred in embodiments that the siloxane be a siloxane other than acyclic hydrogen-polysiloxane compounds, such as tetramethyldisiloxane and polymethylhydrosiloxane, or a cyclic hydrogenpolysiloxane such as 1,3,5,7-tetramethylcyclotetrasiloxane. However, where such compounds are used as anti-scar agents in embodiments of the present invention, it is preferred that the compounds be used in amounts of less than 0.001 parts by weight, or more than 10 parts by weight, based on 100 parts by weight of the adhesive component, i.e., the polymerizable monomer compound.
In addition the ability to prevent, reduce or remove scars, the above agents can also serve as friction reducing agents or slip additives. Thus, in addition to preventing, reducing or removing scar tissue, the above agents can also reducing the composition's coefficient of friction.
Examples of formulations of the invention are presented in the following Table I in which the α-cyanoacrylate monomer is stabilized with anionic and radical stabilizers, and the composition includes a colorant, 0.5% or less of each of methyl paraben and BHA as preservatives, and is packaged in a post-fluorinated HDPE container.
Monomer (Wt %)
(Wt %)
(Wt %)
n-butyl CA (75)
n-butyl CA (75)
n-butyl CA (75)
n-butyl CA (75)
n-butyl CA (75)
n-butyl CA (75)
n-butyl CA (75)
n-butyl CA (75)
2-octyl CA (75)
2-octyl CA (75)
2-octyl CA (75)
2-octyl CA (75)
2-octyl CA (75)
2-octyl CA (75)
2-octyl CA (75)
2-octyl CA (75)
Elongation of 2-Octyl Cyanoacrylate Film
Elongation at Break
Peak Stress (psi)
Modulus (psi)
1370 +/− 41
3.1 +/− 1.6
18624 +/− 703
1035 +/− 77
7.0 +/− 1.5
12343 +/− 502
686 +/− 95
10.5 +/− 1.4
5753 +/− 353
441 +/− 65
11.3 +/− 2.0
3189 +/− 316
Film tensile properties were tested using a MTS Sintech 2/G mechanical testing machine with TestWorks software version 3.08. The procedure used for this determination is a modified version of ASTM D882-95a (Standard Test Method for Tensile Properties of Thin Plastic Sheeting). A 10lbf load cell was used to determine these properties with a constant crosshead speed of 3.0 inches/minute. Small pneumatic grips were used to clamp the film on each end. The size of the films was 4 inches�0.5 inches with variance in thickness. A gage length of 3 inches was used, allowing 0.5 inches of each end of the film to be secured in the grips. Elongation at break, peak stress and modulus were calculated using this procedure.
This table demonstrates improved elasticity and elongation that may be achieved by way of the invention.
Solubilities of TMDS and OMTS in 2-Octyl Cyanoacrylate
TMDS solutions
TMDS films
OMTS films
Slightly Cloudy
Slightly Cloudy
This table demonstrates higher levels of soluble PDMS achievable by way of cyclic PDMS embodiments of the invention.
While the invention has been described with reference to preferred embodiments, the invention is not limited to the specific examples given, and other embodiments and modifications can be made by those skilled in the art without departing from the spirit and scope of the invention.
|Cited Patent
|Filing date
|Publication date
|Mar 10, 1954
|Oct 25, 1955
|Eastman Kodak Co
|Method of making alpha-cyanoacrylates
|Sep 9, 1960
|Dec 14, 1965
|President And Directors Of Geo
|Method for adhesively securing together skin and other soft tissue and bone
|Dec 9, 1960
|May 31, 1966
|Eastman Kodak Co
|Esters of alpha-cyanoacrylic acid and process for the manufacture thereof
|Jun 10, 1968
|Jan 12, 1971
|Eastman Kodak Co
|Esters of 2-cyanopenta-2,4-dienoic acid and polymers thereof
|May 25, 1972
|Feb 24, 1976
|Johnson & Johnson
|Cross-linked cyanoacrylate adhesive compositions
|Apr 23, 1975
|Dec 7, 1976
|Ethicon, Inc.
|Surgical adhesives
|Sep 16, 1977
|Jan 1, 1980
|Applied Science Corporation
|Method for direct bonding of orthodontic structures to teeth using flouride pretreatment
|Sep 23, 1980
|Feb 2, 1982
|Japan Synthetic Rubber Co., Ltd.
|Instant-setting adhesive composition
|Mar 16, 1981
|Dec 21, 1982
|Toagosei Chemical Industry Co., Ltd.
|Novel 2-cyanoacrylate, process for producing same and curable composition comprising same
|Aug 31, 1983
|Oct 16, 1984
|Loctite Corporation
|Thixotropic cyanoacrylate compositions
|Aug 13, 1984
|Aug 6, 1985
|Loctite Corporation
|Thixotropic cyanoacrylate compositions
|Nov 14, 1983
|Dec 24, 1985
|Minnesota Mining And Manufacturing Company
|Cyanoacrylate adhesive composition having sustained toughness
|Sep 16, 1985
|Jan 13, 1987
|Loctite (Ireland) Limited
|Instant adhesive composition utilizing calixarene accelerators
|Apr 8, 1985
|Mar 17, 1987
|Bayer Aktiengesellschaft
|Stabilized cyanoacrylate adhesives containing bis-trialkylsilyl esters of sulfuric acid
|Jul 11, 1986
|Aug 11, 1987
|Ohara Paragium Chemical Co., Ltd.
|Adhesive composition
|Nov 1, 1985
|Nov 10, 1987
|Nippon Shiken Dental Co., Ltd.
|Polymerization composition containing vinyl benzoic acid or a derivative thereof and a vinyl compound
|Jun 27, 1986
|Dec 15, 1987
|Koatsu Gas Kogyo Co., Ltd.
|α-cyanoacrylate adhesive composition of matter
|May 4, 1987
|Jan 19, 1988
|Matsumoto Seiyaku Kogyo Kabushiki Kaisha
|Adhesive composition comprising a cyanoacrylate compound with a silyl isocyanate treated silica gel
|Jan 8, 1987
|Aug 16, 1988
|Ohara Paragium Chemical, Co., Ltd.
|Process for preparing α-cyanoacrylate type compounds and adhesive composition comprising α-cyanoacrylate type compound obtained by the process as its main component
|May 12, 1987
|Jun 6, 1989
|Toagosei Chemical Industry Co., Ltd.
|Cyanoacrylate compositions
|Jun 27, 1985
|Mar 6, 1990
|Loctite Corporation
|Instant adhesive composition and bonding method employing same
|Oct 17, 1988
|Mar 27, 1990
|Bayer Aktiengesellschaft
|One component polysiloxane RTV compositions hardening with elimination of oximes
|Apr 24, 1991
|Aug 18, 1992
|Three Bond Co., Ltd.
|Silicon-containing alpha-cyanoacrylates
|Apr 22, 1991
|May 25, 1993
|Nell Edward R
|Adhesive formulation for nonsurgical blepheroplasty
|Apr 10, 1992
|Sep 28, 1993
|Ohara Paragium Chemical Co., Ltd.
|Adhesive composition consisting primarily of α-cyanoacrylate compound
|Mar 31, 1993
|Jul 12, 1994
|Tri-Point Medical L.P.
|Biocompatible monomer and polymer compositions
|Jan 5, 1993
|Dec 13, 1994
|Ohara Paragium Chemical Co., Ltd.
|Adhesive composition
|Mar 11, 1994
|Jan 31, 1995
|Loctite Corporation
|Di-α-cyanopentadienoate disiloxane compounds for use in adhesives
|Mar 22, 1994
|May 7, 1996
|Tri-Point Medical L.P.
|Biocompatible monomer and formaldehyde producing polymer compositions
|Jun 5, 1995
|May 7, 1996
|Tri-Point Medical L.P.
|Biocompatible monomer and formaldehyde producing polymer compositions
|Jun 5, 1995
|Nov 19, 1996
|Tri-Point Medical Corporation
|Biocompatible monomer and polymer compositions
|Jun 5, 1995
|Dec 10, 1996
|Tri-Point Medical, Corporation
|Biocompatible monomer and polymer compositions
|Jun 7, 1995
|Apr 29, 1997
|Tri-Point Medical Corporation
|Method of hemostatic sealing of blood vessels and internal organs
|Jun 7, 1995
|Jul 27, 1999
|Closure Medical Corporation
|Impregnated applicator tip
|Dec 23, 1999
|Feb 6, 2001
|Closure Medical Corporation
|1,1-disubstituted ethylene adhesive compositions containing polydimethylsiloxane
|Oct 14, 1986
|Mar 14, 1989
|Loctite Corporation
|Thixotropic cyanoacrylate compositions
|Jul 13, 1993
|Aug 24, 1994
|Shiseido Company Limited
|Composition for dermatologic preparation
|Nov 14, 1996
|May 21, 1997
|Dow Corning Corporation
|Spontaneously formed clear silicone microemulsions
|Title not available
|Title not available
|Title not available
|Title not available
|Title not available
|Title not available
|Title not available
|Title not available
|Title not available
|Title not available
|Title not available
|Title not available
|Jan 19, 1999
|Aug 26, 1999
|Closure Medical Corporation
|Electron beam sterilization of liquid adhesive compositions
|Citing Patent
|Filing date
|Publication date
|Oct 20, 2006
|Oct 28, 2008
|Ethicon Endo-Surgery, Inc.
|Adhesive applicator
|Oct 25, 2006
|Feb 9, 2010
|Ethicon Endo-Surgery, Inc.
|Adhesive applier with articulating tip
|Oct 20, 2006
|Jul 6, 2010
|Ethicon Endo-Surgery, Inc.
|Stomach invagination method and apparatus
|Nov 8, 2006
|Nov 16, 2010
|Ethicon Endo-Surgery, Inc.
|Fluid plunger adhesive dispenser
|Nov 1, 2006
|Feb 22, 2011
|Ethicon Endo-Surgery, Inc.
|Use of biosurgical adhesive on inflatable device for gastric restriction
|Oct 18, 2006
|Mar 29, 2011
|Ethicon Endo-Surgery, Inc.
|Use of biosurgical adhesive as bulking agent
|Oct 4, 2006
|Dec 10, 2013
|Ethicon Endo-Surgery, Inc.
|Use of an adhesive to treat intraluminal bleeding
|Feb 25, 2010
|Dec 17, 2013
|Ethicon Endo-Surgery, Inc.
|Methods and devices for treating morbid obesity using hydrogel
|Nov 1, 2006
|Nov 4, 2014
|Ethicon Endo-Surgery, Inc.
|Anastomosis reinforcement using biosurgical adhesive and device
|Dec 9, 2014
|Jan 5, 2016
|Englewood Lab, Llc
|Polysilicone base for scar treatment
|Sep 28, 2012
|Apr 5, 2016
|3M Innovative Properties Company
|Conformable coating and composition
|Dec 22, 2015
|Aug 16, 2016
|Englewood Lab, Llc
|Polysilicone base for scar treatment
|Aug 29, 2003
|Mar 3, 2005
|Onami, Llc
|Self-contained system and method for substance application
|May 4, 2005
|Dec 4, 2008
|Queensland University Of Technology
|Functionalised Siloxanes for Scar Tissue Treatment
|Dec 6, 2006
|Dec 10, 2009
|Hisaki Tanaka
|Dental resin-based cement composition
|Nov 17, 2006
|Mar 4, 2010
|Scuderi Nicolo
|Cosmetic product for the treatment of cicatricial tissues
|Sep 28, 2012
|Jun 4, 2014
|A conformable coating and composition
|U.S. Classification
|424/401, 424/78.03, 424/78.02
|International Classification
|Cooperative Classification
|European Classification
|May 1, 2001
Owner name: CLOSURE MEDICAL CORPORATION, NORTH CAROLINA
Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:NARANG, UPVAN;REEL/FRAME:011764/0600
Effective date: 20010404
|May 24, 2006
|Fee payment
Year of fee payment: 4
|Mar 3, 2010
Owner name: ETHICON, INC.,NEW JERSEY
Free format text: MERGER;ASSIGNOR:CLOSURE MEDICAL CORPORATION;REEL/FRAME:024024/0182
Effective date: 20091221
Owner name: ETHICON, INC., NEW JERSEY
Free format text: MERGER;ASSIGNOR:CLOSURE MEDICAL CORPORATION;REEL/FRAME:024024/0182
Effective date: 20091221
|May 7, 2010
|Fee payment
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|May 7, 2014
|Fee payment
Year of fee payment: 12


text:
If you want an effective weight loss program, then hire a proficient personal trainer. One that can help you step in the right direction. After assessing your fitness level and knowing your health goals, the trainer will create a program that keeps you motivated for the long haul. One that will push you out of your comfort zone and make sure you show up at the gym each week.
Losing weight and changing habits is a hard task, especially, if you are trying to do it alone. That is why there is a need to have someone by your side, who will guide you through the weight loss process.
The key to weight loss; is not to use food as emotional filler. Develop a healthy eating habit; start on a sound exercise program. A daily visualization practice of your end objective will guide you towards safe and quick weight loss to last a lifetime.
Another effective weight loss method is through acupuncture. It has been practiced in China for thousands of years and has spread throughout the world. Aside from losing weight, it also provides therapeutic benefits such as stress management and pain reduction.
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Acupuncture is especially good for promoting the body's ability to heal and recuperate. Studies have shown that acupuncture can induce a relaxation response, which decreases heart rate, lowers blood pressure, improves digestion, eases migraine pain, reduces stress, and best of all; leaving you feeling more energetic.
Yoga combines a unique blend of physical postures,
breathing exercises, meditation and a working philosophy for living. Studies have shown that certain yoga poses may help reduce back pain and get you back on your feet again. A regular yoga practice might have other health benefits such as weight loss, lower blood pressure, as well as help with anxiety and depression. The yoga secret to longevity and well-being is to keep the spine flexible; a flexible spine translates to a flexible lifestyle.
Pilates is a system of movement, strengthening and flexibility.
Pilates exercises will take your workout to a whole new level. One that allows you to get in touch with "your core" - the deep abdominal muscles that support the spine and your movements. A sound and safe Pilates exercise practice shows tremendous results in providing relief from chronic back pain.
If you are experienced or a novice, in your early 30's or late 70's; it´s never too late nor too early to carve-out a path to create a healthier and more balanced lifestyle.
Do any of these resonate with you: You are having a hard time keeping up with your weight loss program? You have started diets, only to struggle sticking to them? As a result, you gain all the weight you managed to lose and more. Are you suffering from pain due to bad posture or incorrect exercise? Or, are you feeling tired and stressed out each day after work? If your answer is yes to any of the questions, then you are in the right place!


text:
Townhouse for Sale
- About this property
- Explore Mount Waverley
Last Chance for Stamp Duty Savings for Investors!Property ID 1553439View details and floorplan in our office: Ray White Oakleigh, 7-9 Atherton Road, Oakleigh VIC 3166
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All three Townhouses have been designed with A contemporary open plan design, sees the kitchen equipped with stainless steel appliances and waterfall stone benchtop, opening onto a timber flooring dining and living area before flowing onto an entertainer's merbau deck and landscaped garden, an upstairs retreat, huge laundry and luxurious main bathrooms crafted with floor-to-ceiling tiling, a semi-frameless shower and spa bath.
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Disclaimer: We have in preparing this document used our best endeavours to ensure that the information contained in this document is true and accurate, but accept no responsibility and disclaim all liability in respect to any errors, omissions, inaccuracies or misstatements in this document. Prospect purchasers should make their own enquiries to verify the information contained in this document.? Purchasers should make their own enquires and refer to the due?diligence?check-list?provided by Consumer?Affairs.? Click on the link for a copy of the due?diligence?check-list?from Consumer Affairs. http://www.consumer.vic.gov.au/duediligencechecklist
Due diligence checklist - for home and residential property buyers


text:
Click to Watch in HD > Soarinfans Youtube Advent Calendar 2016 Day 1
Watch Soarinfans Youtube Advent Calendar 2016 Day 1 Subscribe https://www.youtube.com/user/soarinfa... Soarinfans Youtube Advent Calendar 2016 Day 1 Welcome to mu youtube advent calendar for Christmas 2016 each day we will feature disney youtube families and youtubers from around the world so please tune in each day to meet a new family and share new videos To launch Soarinfans Youtube Advent Calendar for 2016 we invite you to meet Alisa, Jason, Ethan, Cameron and Colby , the family from the youtube channel EECC Travels https://www.youtube.com/channel/UChmD8EWwltkAl4APZC9htOQ/videos Welcome to our new channel! We are a family who enjoys traveling and we want to share our trips and experiences. Check out our playlists to see the adventures we have been on: 2016: Disney World in January: hubby and wifey anniversary trip 2016: Cruise in March/April aboard the Carnival Freedom to Cozumel, Grand Cayman and Jamaica - VLOGS CURRENTLY BEING ADDED EVERY THURSDAY!!! 2016: Disney World in September: family trip 2015: Cruise in April aboard the Carnival Magic to Montego Bay, Jamaica, Grand Cayman and Cozumel, Mexico 2015: Disney World and Universal Studios in September (note: these two trips were recorded with a GoPro so the audio is not great and they were recorded for family memories, so they are not in a vlog format. Please enjoy them as they are.) Look for us on Instagram and Facebook and Twitter! Or email us at
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This lightweight reader features a flexible frame for those who tend to be rough with their glasses. The retro round frame has a matte finish and rivet detail. Each lens is clear with a magnified bifocal portion in your power choice.
- Anti-Reflective Lens Coating
- TR-90 Frame
- Flat Top Bifocals


text:
Thankfully, Chris Brown is Doing Everything in His Power To Ensure That He Never Gets Laid Again
Noted window smasher and Rihanna beater Chris Brown just keeps making it easy to hate him. And he's also helpfully adorning his body with new and horrifying signs of his own d-baggery. Witness this classy smiley-face-on-crack tattoo Mr. Brown just got tattooed on his back. Yeah, not cool, guy, but at least you've offered up a nice little external visual cue to your internal crappiness. [Gawker]