text:
Friday, July 26, 2019
Happy Birthday Chimnezelumndo
Today July 26th is my Birthday and I just give thanks to God for keeping me despite all the Odds......Please say a word of prayer for me and give thanks to God on my behalf...........
Happy Birthday Beautiful one...God's eyes are on you.
40 comments:
- Anonymous26 July 2019 at 12:31
Happy birthdayReplyDelete
Happy birthday zee world telemundo. LlnpReplyDelete
- Anonymous26 July 2019 at 12:34
Happy birthday, we thank God for an added year to you.ReplyDelete
Happy birthday dear!ReplyDelete
happy birthday more years and more wins..your name..can't pronounceReplyDelete
- Elizabeth Bathory26 July 2019 at 12:48
Have birthday Telemundo 😁😁😁ReplyDelete
- Anonymous26 July 2019 at 12:49
Whats the meaning of your name?I am Igbo. Ndù is life but yours ends with ndo, so dont get the last part.You are so beautiful.ReplyDelete
Happy bday to you dear.
Happy birthday dearReplyDelete
I love your name, that's the main I had to comment.
Chimnezelumndo - God provides my shade.
I'm not even sure I translated it well
Happy birthday to you babe, many more years to come.ReplyDelete
Your name look like telemundo.
Happy Birthday BeautifulReplyDelete
Happy birthday to you,God bless your new year !ReplyDelete
Happy birthdayReplyDelete
Happy birthday beautiful Lady, omg she's so prettyReplyDeleteReplies
- Anonymous26 July 2019 at 14:25
As you wan scatter my head abi? see na, my head is swollen and big, I am blushing real hard, thank you so much dear... I appreciate dearDelete
You sure??Delete
Hbd chinezelemundoReplyDelete
Happy birthday beautiful womanReplyDelete
Happy birthdayReplyDelete
Happy birthday. live long and prosper.ReplyDelete
Happy birthdayReplyDelete
Happy birthday. Lol your name almost sounding like Telemundo 😁ReplyDelete
- Anonymous26 July 2019 at 14:20
I can't thank you all one by one, but I am immensely happy, thanks to my lovely Auntie Stella, thanks my SDK family, I am so happy to be counted amongst the living, God gave me a 2nd Chance, grace kept me, mercy paved way for me, Auntie Stella became my small god, SDK family became my pillar.... whether telemundo or Zee world, the name simply means that God is my shelter and shade and he has kept his every promise concerning my life... thank you all for your wonderful wishes, I hide here de read commentsReplyDeleteReplies
Happy birthdayDelete
I wish you all the best
A happy birthday to you our Dearest, like Stella said, God's eyes are on you, the enemy has lost the battle over your life and you will continue to win your every battle in Jesus Christ name... Amen... Happy Birthday and continue being under God's shade and shelter just like your nameReplyDelete
What a beautiful name u have got. mbok whats the meaning? hbd dear age with grace.ReplyDelete
Happy birthday beatifulReplyDelete
Happy Birthday Beautiful, May God continue to bless and keep you, may you have peace which passth human understanding,Amen.ReplyDelete
- Anonymous26 July 2019 at 15:20
Which kind 26? Abi 36. HBD.ReplyDeleteReplies
- Anonymous26 July 2019 at 16:42
it's nobody's fault that you are blind, nobody wrote her age there, that's her birth date, if you want to know her age, contact her and who knows she will fill you in on it... bitter fellowDelete
Happy birthday dearest. Greater,bigger and better you.ReplyDelete
Happy birthday prettyReplyDelete
- goodvibesonly26 July 2019 at 15:49
Happy birthday dearReplyDelete
Disclaimer: Comments And Opinions On Any Part Of This Website Are Opinions Of The Blog Commenters Or Anonymous Persons And They Do Not Represent The Opinion Of StellaDimokoKorkus.com
Pictures and culled stories posted on this site are given credit and if a story is yours but credited to the wrong source,Please contact Stelladimokokorkus.com and corrections will be made..
If you have a complaint or a story,Please Contact StellaDimokoKorkus.com Via
Mobile Phone +4915210724141


text:
Accommodation in Travaco Siccomario
Find a place to stay
Find out more about Travaco Siccomario
Where to stay in Travaco Siccomario
What's Travaco Siccomario like?
If you're looking to discover somewhere new, look no further than Travaco Siccomario. Whether you're planning to stay for a night or for the week, the area around Travaco Siccomario has accommodations to fit every need. Search for hotels in Travaco Siccomario with Hotels.com by checking our online map. Our map displays the areas and neighborhoods around all Travaco Siccomario hotels so you can see how close you are from landmarks and attractions, and then refine your search within the larger area. The best Travaco Siccomario hotel deals are here with our lowest price guarantee.
What types of hotels are available in Travaco Siccomario?
We have Travaco Siccomario accommodations with prices starting at AUD 18. Choose one of our 5411 deals and get discounts of up to 65%.
Below are the number of accommodations by star rating in Travaco Siccomario and the surrounding area:
- • 25 5-star accommodations from AUD 301 per night
- • 192 4-star accommodations from AUD 107 per night
- • 152 3-star accommodations from AUD 88 per night
- • 54 2-star accommodations from AUD 79 per night
- • 31 1-star accommodations from AUD 39 per night
How to Get to Travaco Siccomario
What is the closest airport to Travaco Siccomario?
- • Milan (LIN-Linate), 22.3 mi (35.9 km) from central Travaco Siccomario
Things to See and Do in Travaco Siccomario
What is there to see near Travaco Siccomario:
- • Ponte Coperto (2.2 mi/3.5 km from the city center)
- • Cathedral of Pavia (2.5 mi/4 km from the city center)
- • University of Pavia (UNIPV) (2.6 mi/4.2 km from the city center)
- • Chiesa di San Pietro in Ciel d'Oro (2.9 mi/4.7 km from the city center)
- • 7 Laghi Kart (6.4 mi/10.3 km from the city center)
What is there to do near Travaco Siccomario:
- • San Teodoro Basilica (2.4 mi/3.9 km from the city center)
- • Santi Primo e Feliciano Church (2.3 mi/3.7 km from the city center)
- • Church of San Giovanni Domnarum (2.6 mi/4.2 km from the city center)
- • San Lanfranco Church (2.8 mi/4.5 km from the city center)
- • Museum of Electrical Technologies of Pavia (3.9 mi/6.3 km from the city center)
When is the best time to visit Travaco Siccomario?
- • Hottest months: July, August, June, September (average 81°F)
- • Coldest months: January, February, December, March (average 34°F)
- • Rainiest months: October, November, June, and April (average 4.27 inches of rainfall)

subset: commoncrawl


text:
Rashad Richey Real Talk: Why Is Trump is Messing With The US Census?
Read Rashad's latest commentary
You're about to get a US Census questionnaire…Trump and his administration are fighting like hell to include a question about citizenship. The US Census is constitutionally mandated to count population… not just citizens. Why is this an important distinction?
Census data is used to decide how much money state and local governments get for infrastructure, social services, education, and housing. You see, population creates economic impact regardless of citizenship. The proposed citizenship question has been controversial because it would result in an undercount of the population. That means less money for your community. The Trump administration maintained that citizenship data was necessary to help enforce the Voting Rights Act, which is straight bull. Let me know your thoughts, go to V-103.com and sound off!


text:
Nutritional supplementation could also be necessary to attaining your well being targets, and this dispensary supplies convenient access to the highest high quality supplements from a trusted source. If he wish to purchase a domain with the word SEARCH ENGINE OPTIMISATION is I needed to engender a domain-polinfor positioning -+ or establishment name phrase. All of the accessible information on the potential results on financial operators and customers of the setting of maximum quantities of vitamins and minerals in foods, together with meals supplements, shall be taken into consideration.
With that stated, the FDA maintains a listing of tainted or probably dangerous merchandise marketed as dietary supplements. Hairburst hair vitamins combine natural elements to keep your hair trying healthy and Bootea offer energising teas to keep you motivated and active.
The Food and Drug Administration just isn't authorized to review supplements for safety and efficacy earlier than they hit the market. Scientific evidence reveals that some dietary supplements are useful for overall health and for managing some health conditions.
If he would like to come by a dominion with the recommendation SEARCH ENGINE OPTIMIZATION is I had to sire a domain-polinfor positioning -+ or troop popularity word. Listed here are eleven natural vitamins and supplements that will enhance your vitality. For people with persistent fatigue syndrome, melatonin supplements have been shown to enhance concentration and power whereas lowering fatigue ( 60 , sixty one , 62 ).
Some teams of the inhabitants are at better threat of not getting enough vitamin D, and the Division of Health recommends these individuals take day by day vitamin D supplements. If he would like to purchase a property with the news WEBSITE POSITIONING is I had to engender a domain-polinfor positioning -+ or company reputation word.… Read More


text:
NVIDIA GeForce GTX 960 Video Cards (ZOTAC and MSI) in SLI (Page 1)
The surprising Maxwell-powered GeForce GTX 960s act insanely well in SLI, providing 4K 60FPS gaming in most of the latest games on the market.
When I first started hearing about the new GeForce GTX 960 from NVIDIA, I wondered how the cards would perform in SLI. At first, the 128-bit memory bus worried me, so did the 2GB of VRAM. But during our first review of the ZOTAC GeForce GTX 960 AMP! Edition, we saw that the 128-bit memory bus was definitely not holding back the mid-range GPU.
So what we did, was re-run all of our benchmarks; 1080p, 1440p and even 4K with two GeForce GTX 960s in SLI. The new GTX 960s can only be run in 2-way SLI, else we would've tried to have included some 3- and 4-way numbers. But still, two of these mid-range $199-$209 video cards have some damn impressive performance numbers.
I did some light reading across the Internet over the weekend looking at SLI numbers, and while people have a good point as to 'why would you SLI the GTX 960s together' it's all part of the fun. You can find our final thoughts at the end - there are some very surprising results that you're going to want to see, so let's dive right into it.
For our SLI testing, we used the ZOTAC GeForce GTX 960 AMP! Edition and the MSI GeForce GTX 960 GAMING 2G OC video cards. Everything else stays the same, but we had to tweak the clock speeds on our cards to match them together as there's a 50MHz Base Clock speed difference between them. Once they were matched together, we kicked things off.
PRICING: You can find the Zotac GeForce GTX 960 AMP! Edition 2GB for sale below. The prices listed are valid at the time of writing but can change at any time. Click the link to see the very latest pricing for the best deal.
United States: The Zotac GeForce GTX 960 AMP! Edition 2GB retails for $229.00 at Amazon.
PRICING: You can find products similar to this one for sale below.
United States: Find other tech and computer products like this over at Amazon.com
United Kingdom: Find other tech and computer products like this over at Amazon.co.uk
Australia: Find other tech and computer products like this over at Amazon.com.au
Canada: Find other tech and computer products like this over at Amazon.ca
Deutschland: Finde andere Technik- und Computerprodukte wie dieses auf Amazon.de
- Page 1 [Introduction]
- Page 2 [Testing Method & Test System Configuration]
- Page 3 [Synthetic Benchmarks (3DMark and Heaven)]
- Page 4 [Game Benchmarks (1080p)]
- Page 5 [Game Benchmarks (1440p)]
- Page 6 [Game Benchmarks (4K)]
- Page 7 [Game Performance Summary]
- Page 8 [Power Consumption and Sound Testing]
- Page 9 [Final Thoughts]


text:
Slovenian cycling embroiled in intl doping scandal
Ljubljana, 23 May - After two Slovenian cyclists were suspended over blood doping suspicion last week, the world body for sports cycling, UCI, is now focussing its investigation on the Slovenian cycling connection to the Operation Aderlass blood doping ring. Slovenian police are also taking part in the international investigation led by Germany.
The rest of this news item is available to subscribers.
The news item consists of 2.261 characters (without spaces) or 412 words words.
Buy the news item. Price: 2 tokens; on account: 0 tokens.


text:
In case you are in search of a hen tattoo, then you could have come to the precise place. Fowl tattoos are one of the vital common tattoos designs out there. They've been round for 100 years in numerous varieties for folks to select from.
Again within the day the one time you ever noticed hen tattoos have been on the arm of a sailor or a fisherman however occasions actually have modified. Each women and men are sporting hen tattoos in many various varieties. They're rising in popularity due to their inventive design. They arrive in lots of shapes and types and could be applied into any tattoo design. In case you are in search of one thing religious or inspirational, then the hen tattoo is ideal because it's all the time been seen as a robust metaphor for human life and human feelings. They symbolize the various phases of our lives.
Below are 90+ adorable bird tattoo designs for the bird lover:


text:
1. Follow the smell. Get rid of the dead cat under the sofa first.
2. Don't break the law. Read the news. You must pay the cleaner at least $1,000 now.
3. To create more room for you to spring clean, remove every piece of junk first... except your mother-in-law.
4. Harry Potter is a liar. Don't believe him. You still need to do all the work because that broom of yours isn't going to move on its own.
5. Use a large pail to store your soap water. If one's not available, a 20-piece chicken bucket from KFC will do.
6. Do not, we repeat, do not throw the couch out of the window. A couch is strictly for sitting. Not for flying.
7. Do not be too sentimental. Don't be too attached to things. Unless it's your life-support ventilator.
8. Aiyah, just don't invite anybody to your place lor. Photoshop your "my beautiful home" pics on Facebook. Problem solved.


text:
Body Contouring
At ZR Med Spa we believe confidence plays an important role in our lives, and therefore we offer a non-invasive body contouring treatment that is conduced by sessions until you achieve your desired body shape. We understand that life can get quite busy sometimes which can make it difficult to make regular visits to gym. Our body contouring service will allow you to obtain the same results as going to the gym except sooner, and better.
ZR licensed specialists will work with you to target and eliminate the most troublesome flaws of the torso, and reshape your body to look more attractive. We offer break through non-invasive cosmetic technologies that will get the superior results you've been searching for but weren't sure were actually possible.
Each 60 minutes session is equivalent to results normally attained by several hours of intense physical exercise.
We also offer similar type of treatment to get rid of excess fat/loose skin on the Jaw area (double chin).
Our Treatment:
What to expect from our treatment? Through our body contouring service you'll be able to shape your body to your liking by toning your abdomen, decreasing your waistline, increasing the size of your glutes, toning your tights, and more.
Our treatment can work in increasing or toning the muscles of your abdomen, triceps, biceps, trapezius, pectorals, quadriceps, calves, glutes, hams, and more to obtain your desired figure.
Our body contouring treatment has the ability to tone and tighten areas through electrode pads placed on the skin. These frequencies delivered on the targeted areas can have the health benefits of:
Toned muscles
Improved circulation
Smoothes cellulite
Tighten sagging skin
Burn calories
Increased flow of oxygenated blood
How It Works?
Out body contouring treatment is an exclusive software program that specializes in the body sculpting of targeted areas via skin contact electrodes that deliver waves of pulses with specific frequencies to the targeted areas that result in the sculpting and reshaping of the body. These pulse waves produce powerful muscle contractions that can rehabilitate, strengthen, and tone muscles as well as rapidly reduce fat without the need to go to a gym. Our equipment is FDA Medically approved and it has been highly recommended by doctors due to the no side effects other than the variety of health benefits. This treatment has been used since the 1980's to lose weight fast and it has been largely used by Olympic athletes in order to keep their muscles at peak condition. We have attended several athletes and models that seek to maintain peak condition of their muscles through our treatment.
Frequently Asked Questions:
What should I expect during each session?
The treatment takes place in a private room of the spa where you will lie down to relax as you enjoy the soothing music and the smell of aromatherapy candles. You may go on your phone, read a book, or even nap while you are getting your workout.
Each session includes:
Weekly measurements
One hour sessions
Weekly weigh-ins
Placement of electrode pads on the skin for muscle stimulation
Monitoring by a Medical Esthetician
We recommend to attend our one hour session two to four times per week based on your desired results*. We will provide you with a personalized experience as we target the areas you desire to shape to your liking and remove the stubborn pockets of fat.
*This is an average time as our results will vary from patient to patient depending on their initial body shape when they begin treatment and adherence to program.
When will I see results?
You will visibly see results as soon as in two weeks although this will vary from patient to patient depending what shape they are in when they begin treatment and adherence to the program (They could be more visible at two weeks for patients who adhere to the program more often). You can find out an estimate during your free consultation.
Do I need to follow a diet during this treatment?
We recommend to follow a diet for the best and most effective results. This treatment will do the same job, if not better, as if you were going to the gym at a high intensity every day. Therefore, just like you would want to follow a diet while going to the gym, you also might find that diets and a healthy food choice are always a very good supplement that will get the most out of your treatment.
What is required for me to begin the treatment?
This will also be determined at your free consulation as it varies from patient to patient depending on their shape before the treatment. We do not require you to be completely slim or to have a past gym experience but it is important to note that this treatment can increase muscle mass and induce fat loss in target areas but not all over the body. This treatment is best for those seeking a minor to mild fat reduction or an increase in muscle as desired.
ZR Med Spa offers full set of body contouring techniques that are designed to help you look your best. We have extensive experience in body contouring procedures and are very confident that you will see great improvements in your body while using our body treatment service. Book your free consultation session today to find out how we can help you to achieve your desire look.
Med Spa & Boutique
400 Townline Road,
Mundelein, IL, 60060
Tel: 224-715-1905
Spa Hours
Monday to Saturday: 9:00 a.m. to 6:00 p.m.
Sunday: Closed


text:
|Drug-delivery device comprising certain polymeric materials for controlled release of drug
|Higuchi et al.
|Ocular therapeutic system with selected membranes for administering ophthalmic drug
|Higuchi et al.
|Ocular therapeutic system manufactured from copolymer
|Higuchi et al.
|Method and therapeutic system for treating aqueous deficient dry eye
|Controlled release delivery system by an osmotic bursting mechanism
|Process for improving release kinetics of a monolithic drug delivery device
|Baker et al.
|Intrauterine device for managing the reproductive process
|Higuchi et al.
|Bioerodible drug delivery device
|Theeuwes et al.
|Heller et al.
|Higuchi et al.
|Higuchi et al.
|Process for forming crosslinked oriented, microporous polyolefin film
|Gregorian et al.
|Sodium chloride tablet
This application is a continuation-in-part of application Ser. No. 578,979 filed May 19, 1975, now abandoned which in turn is a continuation-in-part of application Ser. No. 465,276 filed Apr. 29, 1974 and now abandoned, which in turn is a continuation-in-part of application Ser. No. 354,359 filed Apr. 25, 1973 and now abandoned.
(a) is sized and shaped for placement in the environment; and
(b) consists essentially of a mixture that defines a surface of predetermined area that is exposed to the water in said environment, said mixture consisting essentially of
(i) about 1% to about 50% by volume, of discrete depots 0.1 to 250 microns, surface area average diameter, in size of a drug composition that is an osmotically effective solute, said depots being dispered in
(ii) about 50% to about 99%, by volume, of a polymer such that the depots are surrounded substantially individually by a layer of the polymer, the polymer being substantially impermeable to the drug composition, insoluble in the environment at least during the prolonged time period, and permeable to water and having a tensile strength, Young's modulus, and a maximum elongation such that the cohesive strength of said layer is exceeded by the pressure that the depot the layer surrounds is able to generate by imbibing water, whereby when the device is placed in the environment, water is imbibed by the depots in a serially inwardly manner beginning with the depots nearest said surface and said pressure is generated therein, causing the polymer layers surrounding said depots to rupture thereby releasing drug composition therefrom to the environment.
(a) being in the form of a solid unit body that is sized and shaped for placement in the environment;
(b) having a surface of predetermined area, A, that is exposed to the water in said environment when the device is placed therein; and
(c) consisting essentially of a mixture of
(i) about 1% to about 35% by volume of drug composition that when in aqueous solution exhibits an osmotic pressure of at least about 10 atm, has a density, ρ, of about 0.5 to about 8 g/cm3, and is in the form of discrete depots having a surface area average diameter, d, of about 0.1 to about 250 microns, and an average depot-to-depot separation in the mixture of at least about 0.5 microns, with the proviso that ##EQU4## where Φ is the volume percent of drug composition in the mixture, and (ii) about 65% to about 99% by volume of a polymer that has a permeability to water, k, of about 10-8 to about 10-12 g cm/cm2 sec cm Hg, a tensile strength, Ts, of about 200 to about 3000 psi, and a Young's modulus, Y, of about 200 to about 3000 psi and is substantially impermeable to the drug composition and insoluble in the environment at least during the prolonged time period, and, said rate is proportional to ##EQU5## where ρ, Φ, k, A, and d are as defined previously, Δπ is the difference between the osmotic pressures of the drug composition in aqueous solution and the environment, and λ -λ- = 3Ts /Y
wherein Ts and Y are as defined previously, with the proviso that λ is in the range of 1.02 and 4.0, said depots being dispersed in said polymer such that said depots are encapsulated and surrounded substantially individually by a layer of said polymer.
1. Field of the Invention
The present invention relates to a novel device which is useful for releasing drug into aqueous environments of the body. More particularly, the invention relates to a new sustained release delivery device for drugs which enables the release of drugs at a substantially constant rate over a prolonged period of time.
2. Description of the Prior Art
Many sustained release formulations of drug and polymer are described in the medical art literature. Most of these formulations release their drug by either (1) diffusion, in which the drug diffuses through the polymer or the polymer swells with body fluid and the drug is leached from the polymer by such fluid, or (2) erosion, in which the polymer disintegrates or dissolves in body fluids to release entrapped drug. The release of drug from the present invention is not governed by such diffusion or such erosion.
Controlled release drug delivery systems that operate as osmotically driven pumps are also known. For instance, U.S. Pat. No. 3,916,898 describes a system that consists of an osmotically effective drug core encapsulated by a drug impermeable, water permeable coating. The coating has one or more specifically sized outlets in it. The core may consist of a mixture of a drug, such as pilocarpine nitrate, and a polymer binder, such as ethylene-vinyl acetate copolymer. Initially water permeates through the coating to dissolve part of the drug core. Additional water is then imbibed by the core to generate hydrostatic pressure within the core that causes the drug solution to be pumped out through the outlet port(s) in the coating. In contrast the devices of the present invention do not include a coating with defined outlet ports. Instead the present devices consist of a mixture of drug of specific particle size and polymer in specific volume proportions. The parameters governing the release rate of drug from these devices are different than those governing the release rate from the osmotically driven pumps.
U.S. Pat. No. 3,427,066 describes medicinal beads that release drug by a bursting mechanism. The beads consist of a core of water-swellable colloid containing a drug and a thin coating of polymer that is inert to gastrointestinal fluids and permeable to water. When the beads are ingested, water diffuses inwardly through the polymer coating causing the colloid core to swell. This swelling creates sufficient pressure to burst the polymer coating, thereby releasing the entire quantity of drug in the core. The present invention releases drug by a bursting mechanism but not one that involves beads that have a water-swellable colloid core.
U.S. Pat. No. 2,478,182 describes salt tablets in the form of a tablet of compressed salt granules coated with cellulose nitrate of acetate. According to the patent the cellulose derivative penetrates the tablet and forms a honeycomb structure around the compressed granules. Upon ingestion water dialyzes into the compartments of the honeycomb and salt dialyzes out. When the compartments become engorged with water, the compartments burst and liberate salt. The tablets are exhausted in 60-80 minutes. In comparison the devices of the invention provide truly sustained release at a substantially constant rate. The proportion of polymer in the invention devices is grossly larger than that of the salt tablets. Also, the particle size of the sale granules is not in accord with the drug particle specifications of the invention.
The agricultural chemical art literature describes various slow release formulations of fertilizer or pesticide and polymer. Numerous agricultural chemical art references are cited in the files of the above-mentioned cross-reference parent U.S. patent applications. Those references are generally concerned with achieving only slow release of a chemical and are not concerned with the controlled, precise release associated with the present invention. None of these references suggest that chemical is released by a bursting mechanism and the few that mention a release mechanism at all indicate that release occurs via diffusion or erosion similar to that described above.
"Anti-Fouling Paints", Masson, F., J. Applied Chem., Vol. 19, pages 93-99, April 1969, an article totally unrelated to the medical art, describes a mechanism similar to the bursting mechanism by which the present invention releases drug. This article relates to "contact-leaching" marine paints, that is, paints that contain enough pigment for direct contact to occur between adjacent pigment particles in the paint vehicle, such that as one pigment particle is dissolved by the leachate, the adjacent one is exposed to the leachate. It is specifically concerned with explaining the deviation between the actual leaching kinetics and the theoretical leaching kinetics of such paints. A mathematical paint model is proposed consisting of a single, soluble pigment in a stable, insoluble resin vehicle, with the individual pigment particles wet completely by the vehicle. In a layer of such paint, the pigment particles are postulated to be encased in a thin film of resin that exhibits brittle fracture under stress. It is postulated that (a) as one particle is leached from the layer, the thin film of resin that separates it from the adjoining particle is exposed to the leachate, (b) the leachate diffuses through the resin film and dissolves some of the adjoining pigment particle, (c) the resulting osmotic pressure ruptures the film, and (d) the solvated pigment diffuses out through the thus formed interconnecting holes in the layer. This article is believed to be irrelevant to the present invention because it is in an unrelated art and is not concerned with dispensing materials but rather with explaining the leaching kinetics of marine paints.
The invention is a drug delivery device for administering drug continuously to an aqueous body environment for a prolonged time period at a controlled rate. The device is in the form of a solid, unit body that is sized and shaped for placement in the environment and is made at least in part of a mixture that defines a surface of predetermined area that is exposed to the water of the environment, and constitutes a substantial portion of the surface area of the device that is exposed to the water of the environment, said mixture being comprised of about 15% to about 90%, by weight, of discrete depots 0.1 to 250 microns, surface area average diameter, in size of a drug composition that is an osmotically effective solute, the depots being dispersed in about 10% to about 85%, by weight, of a polymer such that the depots are surrounded substantially individually by a layer of polymer, the polymer being substantially impermeable to the drug composition, insoluble in the environment at least during the prolonged time period, and permeable to water, and having a tensile strength, a Young's modulus, and maximum elongation such that the cohesive strength of said layer is exceeded by the pressure that the depot the layer surrounds is able to generate by imbibing water. When the device is placed in the environment, water is imbibed by the depots in a serially inwardly manner beginning with the depots at or nearest said surface, and said pressure is generated therein causing the polymer layers surrounding those depots to rupture thereby releasing the drug composition therefrom to the environment.
Preferred embodiments of the invention release drug at a substantially constant rate. Such embodiments are in the form of a solid unit body that is sized and shaped for placement in the environment and consists essentially of a mixture of (i) about 1% to about 50% by volume of a drug composition that when in aqueous solution exhibits an osmotic pressure of at least about 10 atmospheres and that is in the form of discrete depots having a surface area average diameter, d, of about 0.1 to about 250 microns, with the proviso that: ##EQU1## wherein Φ is the volume percent of drug composition in the mixture and (ii) about 50% to about 99% by volume of a polymer that has a permeability to water at ambient temperature of about 10-8 to about 10-12 g cm/cm2 sec cm Hg, a tensile strength of about 200 to about 3000 psi a Young's modulus of about 200 to about 3000 psi and is substantially impermeable to the drug composition and insoluble in the environment at least during the prolonged time period; the depots being dispersed in the polymer such that the depots are surrounded substantially individually by the polymer. When placed in an aqueous body environment these preferred embodiment release the drug composition to the environment at a rate proportional to: ##EQU2## where ρ is the density of the drug composition and is in the range of about 0.5 to about 8 g/cm3, k is said permeability to water, A is the surface area of the device that is exposed to the environment, Δπ is the difference between said osmotic pressure and the osmotic pressure of the environment, d and Φ are as defined above, and λ2 -λ-4 =(3Ts /Y) (3)
wherein Ts is said tensile strength and Y is said Young's modulus, with the proviso that λ is in the range of 1.02 and 4.0.
In the description of the invention which follows, references will be made to the accompanying drawings wherein:
FIG. 1 is an enlarged cross-sectional view of a delivery device of this invention;
FIGS. 2 and 3 are enlarged cross-sectional views of the device of FIG. 1 after two different periods of use;
FIGS. 4 and 5 are scanning electron photomicrographs of the internal structure of a drug delivery device of this invention taken respectively before and after drug delivery is effected;
FIG. 6 is a partially cut-away enlarged perspective view of an elliptical embodiment of the invention for releasing drugs to the eye;
FIG. 7 is an elevational view of an eye illustrating the use of the devices of FIG. 6;
FIG. 8 is a partially cut-away perspective view of an enclosed tubular embodiment of the device of this invention;
FIGS. 9 and 11 are enlarged elevational views of two devices embodying the invention for releasing drugs intrauterinely;
FIG. 10 is an end view of the exposed end of the devices of FIGS. 9 and 11;
FIGS. 12 and 13 are elevational and cross-sectional views of a substantially enclosed embodiment of the invention;
FIGS. 14 and 15 are elevational and cross-sectional views of another ocular delivery embodiment of this invention;
FIG. 16 is a graph showing the drug release rates of the devices of Example 17 as a function of the volume percent of drug in those devices; and
FIG. 17 is a graph showing the drug release rates of the devices of Example 18 as a function of the surface area average diameter of the drug composition depots of those devices.
Whenever possible, like numbers are used to designate like parts in these Figures.
FIG. 1 depicts one of the more basic embodiments of the invention, namely a drug delivery device 10. Device 10 comprises a plurality of discrete depots 11 of drug composition dispersed through a polymer matrix 12. The polymer of matrix 12 surrounds and encloses the depots 11 and binds them into a solid, unit body. Ideally matrix 12 surrounds depots 11 individually so that each depot 11 is encapsulated by a layer of polymer and is separated from adjacent depots by at least about 0.5 microns. In practice, it is impossible to achieve such ideal dispersion with a large number of depots and there will be some degree of agglomeration of and/or contact between depots within the matrix 12. The phrase "surrounded substantially individually" as used herein is intended to indicate such deviation from the ideal.
The drug composition that forms depots 11 and the polymer that forms matrix 12 meet the specifications stated above. Similarly, the proportion of depots 11 in device 10, is as specified above. The drug composition of depots 11 may be composed of either neat drug that exhibits the specified osmotic pressure, a drug that exhibits insignificant osmotic pressure mixed with a compound that exhibits the specified osmotic pressure, or a drug mixed with one or more compounds that combined exhibit the specified osmotic pressure.
Matrix 12 initially is essentially imperforate so that when device 10 is placed into the body environment no drug composition, except for that located at the surface of device 10 exposed to the environment, is lost by simple dissolution (leaching). And since the polymer forming matrix 12 is substantially impermeable to the drug composition there is substantially no release of drug composition from device 10 by diffusion through the dense polymer.
When device 10 is placed in the environment water permeates through the water permeable polymer forming matrix 12 into the outermost depots (designated 11A in FIG. 2) to dissolve drug composition thereof. The osmotic pressure exhibited by the resulting solution of drug composition in the outermost depots creates an osmotic pressure gradient between the same and the body fluid of the environment. This gradient causes water to be imbibed from the environment into the outermost depots and hydrostatic pressure to be generated therein. FIG. 2 depicts device 10 shortly after it has been placed in a body environment. As shown in FIG. 2 at first only the outermost depots 11A imbibe water instead of all the depots imbibing water equally. When the hydrostatic pressure in a depot exceeds the cohesive strength of the polymer layer surrounding the depot, the layer ruptures, releasing the drug composition contained therein to the environment, as illustrated by ruptured depots 11B. Such rupture causes the depot contents to be released to the environment. After a significant portion of the depot's contents have been so released water begins permeating from the depot inwardly through the polymer to the next innermore depot, and the solution-imbibition-rupture-release sequence described above occurs with respect thereto. This sequence continually repeats itself resulting in a serially inward bursting of depots until the innermost depots eventually are exposed to water and burst.
As shown in FIG. 3 the release of drug composition from device 10 transforms that portion of the device from which the release has occurred into a polymeric lattice. The lattice structure of the exhausted portion of the device is exaggerated in FIG. 3 for the purpose of illustration . Depending upon the elastomeric properties of the polymer forming the matrix, the polymer may relax or retract after such rupture causing the lattice structure to be indiscernible.
It is essential that device 10 include a substantial number of depots if continuous release at a substantially constant rate is to be realized. If there was only one depot, for instance, its uncontrolled rupture would cause the instantaneous pulse release of the entire contents of the single depot. Then number of depots is a function of the depot loading and the size of the depots. Depot size affects the kinetics of drug release from the device and is important as regards the constancy of the release rate and the precision of the release rate. Constancy is an important factor in the quality and effectiveness of many therapies and precision is important as regards facilitating quality control and meeting label representations. Functionally, the depots must not be so small as to (1) inhibit them from being dispersed uniformly in the polymer with a high degree of discreteness, that is, a high degree of individual encapsulation by the polymer, or (2) adversely affect their ability to imbibe sufficient water to burst the surrounding polymer skin. Correlatively, the depots must not be so large as to (1) inhibit them from being dispersed uniformly in the polymer, or (2) make the release rate of drug from the device depend significantly on the rate of dissolution of the drug composition.
As indicated above, the release rate of drug from the preferred embodiments of the invention is proportional to relationship 2 above. Three of the parameters of that relationship, ρ, π, and d, concern inherent properties of the drug composition. The osmotic pressure of the drug composition, π, depends on the solubility of the drug composition in water and the number of solute species the drug composition creates in solution. The surface area average diameter, d, of the depots may be calculated from measurements of the specific surface area of the composition. Such measurements may be made according to the procedures described in the following references. S. Brunauer, P. Emmett, E. Teller, J. Am. Chem. Soc. 60, 309 (1938); S. Gregg, "The Surface Chemistry of Solids", 2nd ed., Reinhold Publishing Corp., N.Y. (1961); S. Gregg and K. Sing, "Adsorption, Surface Area and Porosity", Academic Press, N.Y. (1967); D. Yound and A. Crowell, "Physical Adsorption of Gases", Butterworth and Co. Ltd., London (1962); C. Orr and J. M. Dalla Valla, "Fine Particle Measurements", Macmillan, N.Y. (1959).
The relationship between the specific surface area and the surface area average diameter, d, in microns has been determined to be: d=6/πAs (4)
wherein ρ is as defined previously and is in g/cm3 and As is the specific surface area of the drug composition in m2 /g. It will be appreciated that said specific surface area measurements provide integrated values and that d is thus an average value. Also equation 4 assumes the depots exist as nonporous spheres, and is accordingly an approximation in this respect. Likewise three of the parameters k, Ts and Y (Ts and Y define λ) are inherent properties of the polymer that forms matrix 12. Each of these parameters is measurable by known techniques. The remaining parameters, A and Φ, concern, respectively, the geometry and composition of device 10.
The parameters d and Φ have been found to significantly affect the constancy and precision of the release rate of drug composition from the preferred embodiments. As indicated by relationship 1 above these parameters have interrelated effects on the release rate. When relationship 1 is satisfied and d and Φ fall within the ranges specified above, the release rate of drug composition from the device is substantially constant. That is, the standard deviation in the release rate is no greater than 15% over the period between 20% and 80%, inclusive, cumulative drug release as determined by ten measurements of the release rate taken at equispaced intervals over that period. Otherwise the release rate will be approximately proportional to time-1/2.
In particularly preferred embodiments of the invention π is 10 to 2000 atm, d is 1 to 50 microns, Φ is 5% to 35%, the volume percent of polymer is 65% to 95%, k is 10-9 to 10-10 gcm/cm2 sec cm Hg, Ts is 400 to 1500 psi, Y is 300 to 1500 psi, and the polymer has a maximum elongation of 200% to 1700%.
Polymeric materials for forming the matrix 12 include materials known to the art for making osmosis and reverse osmosis membranes, such as commercially available cellulose acetate and its derivatives, partial and completely hydrolyzed ethylene-vinyl acetate copolymers, highly plasticized polyvinyl chloride, homo- and copolymers of polyvinyl acetate, polyesters of acrylic acid and methacrylic acid, polyvinyl alkyl ethers, polyvinyl fluoride, silicone polycarbonates, aromatic nitrogen-containing polymeric membranes that exhibit water permeability and essentially no solute passage, osmosis membranes made from polymeric epoxides, osmosis membranes made from copolymers of an alkylene oxide and alkyl glycidyl ether, semipermeable polyurethanes, semipermeable polyglycolic or polylactic acid and derivatives thereof, the membranes of ionically associated polyelectrolytes, the polymers formed by the coprecipitation of polycation and polyanion as described in U.S. Pat. Nos. 3,276,586, 3,541,005, 3,541,006, 3,546,142 and 3,173,876, derivatives of polystyrene such as poly(sodium styrenesulfonate) and poly(vinylbenzyltrimethyl-ammonium chloride), and the like. Ethylene-vinyl acetate copolymers, are preferred. It should be understood that the polymer, regardless of its chemical structure, must meet the previously stated specifications to be useful in the invention.
The term "drug" as used herein encompasses any chemical compound or biological agent which may be administered to a patient to aid in the diagnosis, treatment or prevention of disease or to control or improve any pathological or physiological condition. "Drugs" include, without limitation, hypnotics, sedatives, psychic energizers, tranquilizers, anti-convulsants, muscle relaxants, analgesics, anti-inflammatory agents, anesthetics, anti-spasmodics, anti-ulcer agents, anti-microbials, cardiovascular agents, diuretics, anti-neoplastic agents, anti-viral agents, anti-glaucoma agents, and the like. The drug can be in various forms, such as uncharged molecules, components of molecular complexes, pharmacologically acceptable salts such as hydrochloride, hydrobromide, sulfate, phosphate, citrate, nitrate, borate, acetate, maleate, tartrate, salicylate, and the like. For acidic drugs, salts of metals, amines or organic cations, for example quaternary ammonium can be employed.
As noted, the water solubility of the drug is important as regards the drug's ability to generate the specified osmotic pressure in solution. Drugs having a solubility in water of at least 1% by weight usually have such ability. Typical water-soluble drugs include, without limitation, ephedrine hydrochloride, ephedrine sulfate, hydroxy-amphetamine, isoproterenol hydrochloride, cholinecarbamyl chloride, pilocarpine hydrochloride, pilocarpine nitrate, demecarium bromide, echothiophate iodide, physostigmine salicylate, propranolol hydrochloride, homatropine hydrochloride, homatropine methylbromide, methscopolamine nitrate, alverine citrate, chlorophenoxamine hydrochloride, calcium pantotheate, epinephrine bitartrate, chloramphenicol sodium succinate, hydrocortisone phosphate, hydrocortisone sodium succinate, gentamicin sulfate, neomycin sulfate, prednisolone sodium phosphate, tetracycline hydrochloride, polymixin sulfate and the like.
Limited solubility drugs, that is drugs that have a solubility in water of less than 1% by weight, normally are not capable of generating the required osmotic pressure and thus a compound having such a capability must be added to the drug. Even with water-soluble drugs, the addition of such compounds may enable a more precise control of the pressure gradient that is generated, and hence more precise control of the drug release rate. These added compounds are normally essentially pharmacologically inert and include water-soluble inorganic and organic salts and carbohydrates such as magnesium sulfate, magnesium chloride, sodium chloride, lithium chloride, potassium sulfate, sodium carbonate, sodium sulfite, lithium sulfate, calcium bicarbonate, sodium sulfate, calcium sulfate, potassium acid phosphate, calcium lactate, magnesium succinate, tartaric acid, acetamide, choline chloride, soluble carbohydrate such as sorbitol, mannitol, raffinose, glucose, sucrose, lactose, mixtures thereof and the like. Limited solubility drugs which may be delivered by the use of such added solutes include hormones, such as estrogenic and progestational hormones; steroids, such as hydrocortisone alcohol or acetate and prednisolone acetate; and other drugs such as bacitricin, idoxuridine, and clonidine HCl.
Common additives such as pigments, stabilizers antioxidants, surfactants, and binders may be included in the polymer-drug composition depot mixture. However, such additives, in kind and amount, should not affect the basic and novel characteristics of the device. The same may be said for the inclusion of elements other than the mixture in the overall make-up of the device.
Delivery device 10 offers many advantages over conventional drug forms. It provides, in a single device needing only one application, a quantity of drug sufficient for an entire therapeutic regimen. This large quantity of drug may be safely administered at one time without fear of accidental total release by puncture of the device. The device is simple and of potentially inexpensive construction. Importantly, the device may be used in any water-containing patient body environment irrespective of the environment's pH, enzyme activity, or fluid turnover rate. With the erosion and diffusion devices of the prior art, changes in environment conditions, such as a change in the environment's pH as might occur if a device were to pass through the gastrointestinal tract, would effect major changes in the device's release characteristics.
Also, the devices of this invention permit drug release to be continued over prolonged periods of time. Rate of delivery can be adjusted by varying one or more of the parameters of relationship 2 above. The time period over which drug is released may vary widely depending upon the desired therapy. Normally the drug will be released for at least two hours. Ocular insert embodiments of the device will usually release drug for at least 1/2 day, often for up to two weeks. Intrauterine device embodiments for contraception purposes will release drug for months. Thus, the term "prolonged time period" means a period of at least two hours and connotes for a given device the time period over which release is required to achieve the desired therapy.
The present invention potentially finds application in the release of all drugs to all aqueous body environments of a patient. Although not expressly defined hereinbefore, it should be clear that an aqueous body environment can be any body tissue or body cavity, internal or external, which contains an aqueous medium. Typical aqueous body environments include the sacs of the eye, the gastrointestinal tract, the vagina or uterus, muscle tissue or the circulatory system. Devices of this invention may assume a wide variety of shapes, sizes and configurations for insertion, placement and implantation in or administration to these different aqueous body environments as are known in the art.
In one preferred embodiment, the device is in the form of a drug-dispensing ocular insert. A typical ocular insert is shown in FIG. 6 as device 60. Device 60 is illustrated in an elliptical configuration and in an enlarged size. In practice, device 60 would be of a size adapted for insertion and retention in the upper or lower cul-de-sac of the eye, say 6-25 mm long by 4-10 mm wide by 0.1-2 mm thick, and also might assume any shape conducive to such insertion and retention. Such placements are illustrated schematically in FIG. 7.
In FIG. 7, two elliptical ocular device 60 of this invention are depicted positioned for administering drug to eye 70. Eye 70 is comprised of an upper eyelid 71 and a lower eyelid 72, and eyeball 73 covered for the greater part of its posterior area by a sclera 74 and at its central area by a cornea 75. Eyelids 71 and 72 are lined with an epithelial membrane or palpebral conjunctiva, not shown, and sclera 74 is lined with a bulbar conjunctiva which covers the exposed surface of eyeball 73. Cornea 75 is covered with a transparent epithelial membrane, not shown in this figure. The portion of the palpebral conjuctiva which lines upper eyelid 71 and the underlying portion of the bulbar conjunctiva defines an upper cul-de-sac, shown by dotted line 76, while that portion of the palpebral conjuctiva which lines lower eyelid 72 and the underlying portion of the bulbar conjunctiva defines a lower cul-de-sac, shown by dotted line 77 in FIG. 7. The novel drug delivery device 60 of this invention is designed for insertion into cul-de-sac 76 of the conjunctiva between sclera 74 of eyeball 73 and upper eyelid 71 or in cul-de-sac 77 of the conjunctiva between the sclera 74 of eyeball 73 and lower eyelid 72, generally to be held in the drug administration position by the natural pressure of the respective eyelid. Device 60 comprises a water-permeable matrix 12 having dispersed throughout a plurality of discrete depots 11 of a suitable drug composition. The ocular sacs provide a suitable aqueous environment for device 60 to operate in. The tear fluids present in the ocular sacs contain water which is imbibed through matrix 12 into the outermost depots by osmosis, generating pressure within those depots. This pressure eventually bursts the outer depots' enclosing polymer matrix, frees the depots' drug and gives the tear fluids access to underlying depots and so forth. The external result of such serial bursting of the depots is a sustained continuous delivery of drug to the eye.
As indicated above, the shape and size of a delivery device are factors which play a part in the rate at which drug is released from the device. The water imbibition-bursting release mechanism, as has been described, involves drug release from an inward-migrating bursting surface or front. The rate or release is a function of the area of this surface or front. A drug delivery device of the configuration of device 60, by its relative thinness, is essentially a two-dimensional device. Thus, as it releases drug it will present a substantially constant surface area. Assuming that the distribution of depots 11 through the matrix 12 is uniform, this constant surface area should result in a relatively uniform rate of drug release.
Because of the small distance (thickness) through which the bursting front travels during use of a device like device 60, the rate of front travel must be very low, especially when the delivery is substantially prolonged. Such a slow-moving front potentially is unduly subject to disturbance. A configuration of the device of this invention which leads to the presentation of a uniform area for bursting without the potential disadvantages of the device of FIG. 6, is device 80 of FIG. 8. Device 80 comprises a core 81 having a portion of its surface exposed and the remainder of its surface covered with a membrane or coating 82. Core 81 is made up of a plurality of depots 11 dispersed in and enclosed by matrix 12. Depots 11 and matrix 12 act in concert to deliver drug through the exposed area of core 81 by the bursting mechanism described with reference to FIGS. 1, 2 and 3. Membrane or coating 82 is a material substantially impermeable to passage of the drug composition of depots 11 but also impermeable to water. With device 80, the water diffuses into the core substantially through the two exposed ends of the device, and the bursting occurs at two fronts which move from the exposed ends inwardly. The area of the bursting fronts remains essentially constant as they move through device 80. Device 80 is simple to fabricate. A long tube of membrane or coating 82 filled with core 81 can be extruded and cut into suitable lengths.
Another embodiment of the device of this invention is a drug dispensing intrauterine device. FIGS. 9 and 11 illustrate devices of this invention in two of the many art-recognized forms which a uterine retentive device may assume. Device 90 of FIG. 9 is a loop-shaped device of a shape and size suited for insertion through the cervix into the uterus. Device 110 of FIG. 11 is a "T"-shaped device also of a shape and size suited for uterine placement. Device 90 has a structure similar to that of device 80. As shown in FIG. 10, device 90 comprises a core 81 having bonded thereto outer covering 82. Core 81 comprises a polymer matrix containing drug depots in accord with this invention. These details are not shown in FIG. 10. Covering 82 is impermeable to the drug composition of the depots and to the aqueous uterine fluid. Water diffuses into core 81 through the two exposed ends, causing the depots to burst and release their drug contents via said ends. As illusrated by device 110 in FIG. 11, it is of course not required tha both ends of such a device be exposed. In device 110, covered device 80 is affixed to a crossbar 111 to form a "T". Drug depots are present within device 80. The contents of these depots are released serially by bursting as uterine fluids enter the bottom end of the axial arm of device 110 and generate pressure within the depots. Devices 90 and 110 give a drug release which is continuous, prolonged, and at a substantially constant rate. Since the path over which the bursting fronts must travel is relatively long (the length of device 90, for example), a reasonably rapid (and thus less sensitive) rate of front travel may be employed, even over very extended periods of time such as a year or more. Thus, while intrauterine devices embodying the present invention may be used for relatively short term administration of drugs to the uterus, such as 0.5 to 7 days administration of an antibiotic or counterirritant, they may also be used for delivery of drugs to the uterus over extended periods of time such as several months. In this latter application, they find a preferred utility delivering progestational hormones, estrogenic hormones, and antifertility hormonal agents. These hormones are generally not water-soluble so, as noted above, it will generally be necessary to intimately add an osmotically effective solute to the hormone.
Devices 90 and 110 are just two of many possible shapes which the device of this invention might assume for use in the uterus. Other suitable shapes are catalogued in the text Intrauterine Contraceptive Devices, written by Shubeck, et al. and published in 1971 by Massachusetts Institute of Technology, which text is herein incorporated by reference.
In describing devices 80, 90 and 110, reference has been made to their water-impermeable outer walls or barrier membranes. Water permeability is a function of the permeability of the polymer forming the barrier and the thickness of the barrier. Good barrier membranes may be made from polymers that have a water permeability of less than 10-10 (gmcm/cm2 sec cm Hg)
provided the membrane is made sufficiently thick. Such polymers are polyethylene, polyvinylidene chloride, polyvinyl chloride, natural rubber, polyisoprene, polybutadiene, styrene/butadiene copolymers, ethylene/propylene rubbers and tetrafluroethylene polymers. These membranes or walls must be imperforate and thick enough to not be perforated by the bursting taking place within the device core.
With the devices set forth in FIGS. 1-3 and 6-11, a decreasing or constant rate of drug release is obtained. FIGS. 12 and 13 illustrate a device, designated 120, that releases drug at an increasing rate. FIG. 12 is an elevational view of device 120, while FIG. 13 is a cross-sectional view of the same device. Device 120 contains a drug depot-containing polymer core 81 of essentially trapezoidal cross section. Device 120 contains a drug- and water-impermeable outer wall 121 which surrounds the top, bottom and all but one side of core 81. Core 81 is exposed at opening 122.
In use, body fluids initially contact core 81 at opening 122. Depot bursting initially occurs (at t0) at this opening. The bursting front moves inward with time, respectively at sequential times t1, t2, t3, and t4, reaching the points in the core indicated by dotted lines in FIG. 13. The width of the bursting front increases as it moves inwardly. Since the front continues to move at a relatively constant rate, this means that increasing amounts of drugs are released and the rate of release increases.
The invention will be further described with reference to the following examples, which are intended to illustrate the invention and not to limit its scope. Unless indicated otherwise, parts are by weight. Release rates reported in these examples are expressed in terms of the rate of release of the free base form of the drug involved rather than the salt form. The values given for k are at ambient temperature.
A delivery device for the prolonged release of drug (pilocarpine nitrate) to the eye is prepared and tested in the following manner:
(b) Preparation of drug/polymer mixture.
A 7 grams portion of micronized pilocarpine nitrate is admixed with 3 grams of an ethylene-vinyl acetate copolymer (duPont ELVAX 40) containing about 40% vinyl acetate and having a melt index of 45-70 g/min (by ASTM D 1238 - modified test). This copolymer has a tensile strength of about 600-700 psi and an elongation at break of 1400% to 1500%. It is semi-permeable, being impermeable to pilocarpin nitrate but permeable to water. Pilocarpine nitrate is a water-soluble material, (about 25% solubility in water) and functions as an osmotically effective solute. The pilocarpin nitrate particles are on average .about.40 microns in diameter. This mixture is heated to 120° C. and cast into a 0.6 mm thick film.
(b) Production of ocular inserts.
A number of 6 mm discs, suitable in size for installation in the sac of the eye, are cut from the 0.6 mm thick film. These discs have a surface area of 66 mm2.
(c) Testing of inserts.
The inserts are placed in a simulated ocular aqueous environment. The outermost drug depots imbibe water, swell, and burst their enclosing membranes, releasing their drug and exposing innermore depots. The amount of drug released is monitored by an UV spectrometer set at 215 nanometer wavelength. A relatively rapid release of pilocarpine nitrate begins to be noticed. The release continues for about 22 hours at a rate gradually decreasing from an initial 400 microgram per hour to about 250 micrograms per hour after 22 hours. After 22 hours, the release rate falls rapidly. Microscopic and macroscopic comparison of the devices before and after use show that they retain their unit configuration but release drug by bursting the matrix surrounding the drug depots. FIGS. 4 and 5 are electrophotomicrographs of this drug-containing matrix taken before and after drug release respectively, which show the effect of the bursting release.
A partially enclosed ocular drug delivery device is prepared.
First a 100 mil wide by about 20 cm long strip is cut from the 0.6 mm thick pilocarpin nitrate-ethylene-vinyl acetate copolymer matrix prepared in Example 1. This strip is then laminated between two 0.08 mm sheets of water- and drug-impermeable clear polymeric material. Elliptical ocular inserts are punch cut from the laminate straddling the enclosed matrix. The inserts are on their axes 6 mm by 13 mm and have a 13 mm long, 2.5 mm wide and 0.6 mm thick strip of matrix running through their center. Only the 0.6×2.5 mm ends of the matrix are exposed. FIGS. 14 and 15 are elevational and cross-sectional views of such a device, designated 140, showing inner matrix 142 and outer laminate, partial covering 141.
One of these inserts is placed in a simulated ocular environment. Pilocarpine nitrate is released at a continuous controlled rate by the bursting mechanism described above. Visual examination of the devices proves that the bursting is taking place along a gradually migrating front, since the areas having drug present are an opaque white and the drug-exhausted matrix areas are translucent.
During the first two days, the release drops from about 75 micrograms/hour to about 50 micrograms/hour. For six additional days, the drug release rate is between about 50 and about 40 micrograms per hour. After about 200 hours of total test, the drug content is substantially exhausted and the drug release rate trails off to zero micrograms per hour.
To demonstrate the non-sensitivity to environmental conditions of the devices of this invention, one device as prepared in Example 2 is placed in an acidic (pH 4) aqueous environment, another is placed in an alkaline (pH 9) aqueous environment; and one is placed in a sample of aqueous laboratory waste. Even under these conditions, all devices continue to release drug substantially as described in Example 2.
Twenty-five grams of progesterone (10μ particles) is mixed with 25 grams of sodium bicarbonate (10μ particles). The progesterone and NaHCO3 are mixed together in a V-type drug blender for 24 hours. The drug/bicarbonate mixture is added to 50 g of Elvax 40 in a small enclosed mixer and mixed with heating for about 30 minutes. After mixing in the mixer, the intimately blended molten mass is extruded into a 3.8 mm ID polyethylene tube. A 3 cm length of this tube is sealed at one end and is heat bent into a loop configuration in accord with FIG. 9. A 2 cm length is employed as the center bar of a "T"-shaped device by being bonded to a solid polyethylene crossbar in accord with FIG. 10. When placed in human uteri, these devices each release progesterone at a rate of .about.25 micrograms/day. The 3 cm long loop device maintains this rate of release for about four months; the "T" device for about two months. After these periods, the release rate falls.
Three grams of Elvax 40 is mixed with 27 grams tetrahydrofuran to yield a homogenous solution. Into this polymer solution is mixed 7 grams of triethylenethiophosphoramide (40μ sized particles). The drug/polymer/solvent mixture is cast and the solvent is driven off to yield 0.8 mm thick dry sheets. The polymer/drug sheets are cut into 2.4 mm wide strips which are subsequently laminated between two 0.1 mm thick sheets of drug- and water-impermeable polymeric material. Elliptical devices are punched from the laminate straddling the enclosed matrix. The devices, 13 mm long and 6 mm wide, have the 2.4 mm wide and 0.8 mm thick strip of matrix running through the center of the major axis. Only the ends of the matrix are exposed.
The device is implanted surgically directly at the site of the cancerous growth. As body fluids are imbibed by the exposed matrix, the device begins to release triethylenethiophosphoramide at a constant rate of about 2 milligrams/day. After 10 days, the drug will be depleted and the device may be removed.
The experiment of Example 1 is repeated with the change that instead of 7 grams of micronized pilocarpine nitrate, 7 grams of an intimate 50/50 mixture of hydrocortisone acetate and sodium chloride is employed.
The substantially insoluble hydrocortisone acetate alone would not promote sufficient water imbibition to effect bursting. In combination with the soluble salt, however, a bursting release is achieved.
(a) Preparation of drug/polymer mixture.
37.5 parts of the copolymer of Example 1 was dissolved in 150 parts methylene chloride. 12.5 parts tetracycline hydrochloride was mixed ultrasonically with 25 parts methylene chloride. The two mixtures were then combined and the vessels which contained them were rinsed with 10 parts methylene chloride, the rinse being added to the combined mixtures. The entire mixture was blended until the slurry had a smooth texture.
The slurry was cast and prepared into a 250-300 micron film.
(b) Production of ocular inserts.
A number of crescent-shaped (13.3 mm×3.6 mm) inserts were punch cut from the above-described film, each of which contained 33.3 mg tetracycline hydrochloride.
A number of elliptical (5 mm×8 mm) inserts were also punch cut from said film, each of which contained 2.40 mg tetracycline hydrochloride.
(c) Testing of inserts.
The crescent-shaped and elliptical inserts of part (b) were tested by the procedure described in Example 1, part c, with the UV monitoring at 356 nanometer wavelength.
The initial tetracycline hydrochloride release rate from the crescent-shaped inserts was found to be approximately 25 μg/hr. This rate had decreased to between 8-9 μg/hr after 40 hours and then generally leveled into a slowly decreasing curve. After 160 hours the release rate was 4 μg/hr.
The initial release rate from the elliptical inserts was approximately 17 μg/hr. This rate had decreased to about 8 μg/hr after 15 hours and thereafter leveled off in a slowly decreasing curve. After 160 hours, the release rate was about 21/2 μg/hr.
The release mechanism was the same as that observed for the inserts of Example 1.
(a) Preparation of drug/polymer mixture.
A mixture of 85 parts of the polymer of Example 1 and 15 parts isoproterenol hydrochloride (particle size 5-100 microns) solvent case into a film. This film was placed in a shim and melt pressed at 50° C. into a 150 micron thick film.
A 150 micron thick film of a mixture of 70 parts of the polymer of Example 1 and 30 parts isoproterenol hydrochloride (particle size 5-100 microns) was prepared in a similar manner.
(b) Production of ocular inserts.
A number of 6 mm D circular discs were punch cut from the films described above. 450 micron thick laminates of these discs comprising a 70/30 polymer/isoproterenol hydrochloride disc sandwiched between two 85/15 polymer/isoproterenol hydrochloride discs were made by heat pressing the three discs together at 50° C.
(c) Testing of inserts.
The inserts of part (b) were tested by the procedure of Example 1, part (c), with the UV monitoring at 279 nanometer wavelength.
The initial release rate of isoproterenol hydrochloride was 30 μg/hr. This rate decreased rapidly during the first day of the test to about 7 μg/hr, at which it leveled off. After 120 hours, the release rate was still about 7 μg/hr.
The release mechanism was the same as that observed for the inserts of Example 1.
An ocular device for releasing pilocarpine nitrate to the eye was prepared and tested in the following manner.
(a) Preparation of drug/polymer mixture and ocular devices.
A 8.75 g portion of micronized pilocarpine nitrate (ρ=1.36 g/cm3, π=37 atm) was blended with 16.25 g ethylene-vinyl acetate copolymer (duPont ELVAX 210) having a vinyl acetate content of 28% and a melt index of approximately 400 (density=0.94 g/cm3, k=1.9×10-10 g cm/cm2 sec cm Hg, Ts =300 psi, Y=600 psi). Blending was performed in a Brabender Plasticorder half-size internal mixer for 25 minutes at ambient temperature. The resulting blend was passed through the cooled rolls of a 3×8 inch rubber mill to form a rough 0.9 mm thick sheet. 12 g portions of the sheet were compression molded between heated plattens of a hydraulic press at 65° C. for 5 min. to form 0.5 mm thick films. The molded films were surface washed in distilled water and desiccator dried. The pilocarpine nitrate was separated from a sample of the film by dissolving off the polymer and its specific surface area was determined by the above mentioned techniques and the surface area average diameter, d, was calculated to be 1.5 microns.
Elliptical ocular devices having a surface area, A, of 1.2 cm2 were punched from the dry films.
(b) Testing of Devices
The devices were placed in a simulated tear fluid environment and the amount of pilocarpine nitrate released was monitored by a UV spectrometer set at 215 nanometers wavelength. The devices initially released 100 mcg/hr. The rate gradually decreased to 45 mcg/hr at 30 hr and remained stable to 168 hr. After 170 hr, the rate dropped rapidly as the devices were exhausted of pilocarpine nitrate.
(a) Preparation of drug/polymer mixture and ocular devices 6 parts of the polymer of Example 12 was masticated on a roll mill until a film was formed. 4 parts of diethylcarbamazine citrate (ρ=1.3 g/cm3, π=108 atm) was added slowly to the film during further mastication. The mixture was repassed through the mill to obtain a smooth dispersion of the diethylcarbamazine citrate in the polymer. The resulting sheet was placed in a shim and heat pressed at 65° C. for 5 min. into, a 500 micron thick sheet. The surface area average diameter, d, of the diethylcarbamazine citrate was about 5 microns. Elliptical ocular devices 5.8 mm×13.5 mm, A=1.2 cm2, were punch cut from the film.
(b) Testing of Devices
The devices of part (a) were tested by the procedure of Example 12, part (b) with the UV monitoring at 213.5 nm wavelength. The initial release of diethylcarbamazine citrate was about 30 mcg/hr. This rate leveled off after one day to about 25 mcg/hr and this rate held with a slight decrease for about 5 days. After 5 days the release rate decreased rapidly.
(a) Preparation of drug/polymer mixture and vaginal devices 20 g of sodium bicarbonate (ρ=2.16 g/cm3, π=240 atm) were blended with 20 g of the sodium salt of candicidin. Both ingredients of the blend had a surface area average diameter, d of 10 microns. This blend was in turn blended on a rubber mill with 18 g of the copolymer of Example 12 and 42 g of ethylene-vinyl acetate copolymer (DuPont ELVAX 40) having a vinyl acetate content of 40 wt % (density=0.96 g/cm3, k=4.5×10-10 g cm/cm2 sec cmHg, Ts =650 psi, Y=300 psi). The resulting mixture was extruded into a 4 mm diameter rod. Devices 3 cm long were cut from the rod.
(b) Testing of Devices
The devices were placed in a simulated vaginal fluid environment and the amount of the sodium salt of candicidin released was monitored by a UV spectrometer set at 364 nanometers wavelength. After an initial, short priod of unsteady state release the release rate of candicidin-Na was substantially constant at 500 mcg/day-cm2 for about 2 weeks.
(a) Preparation of drug/polymer mixture and ocular devices 24 g of epinephrine bitartrate (ρ=1.5 g/cm3, π=78 atm) were blended with 76 g of the copolymer of Example 12 in an internal mixing bowl. The resultant blend was extruded into a 700 micron thick sheet. The epinephrine bitartrate was separated from a sample of the sheet and its specific surface area was measured by the above mentioned techniques. From this measurement the surface area average diameter of the epinephrine bitartrate particles in the sheet was calculated to be 5 microns. Elliptical ocular devices 10.6×3.8 mm were cut from the sheet.
(b) Testing of Devices
The devices of part (a) were tested by the procedure of Example 12, part (b), with UV monitoring at 279 nm wavelength. After an initial short period of unsteady state release the devices released the drug at a substantially constant rate of 6 mcg/hr for one week.
(a) Preparation of drug/polymer mixture and ocular devices 40 g of tetracycline hydrochloride (ρ=1.45 g/cm3, π=10.3 atm) were blended with 60 g of the copolymer of Example 12. The resultant blend was extruded into a 700 micron thick sheet. The tetracycline hydrochloride was separated from a sample of the sheet and its specific surface area was measured by the above mentioned techniques. From this measurement the average diameter of the drug particles in the sheet was calculated to be 6.1 microns. Elliptical ocular devices 5×8 mm were cut from the sheet.
(b) Testing of Devices
The devices of part (a) were tested by the procedure of Example 12, part (b), with UV monitoring at 356 nm wavelength. After an initial short period of unsteady state release the devices released drug at a substantially constant rate of 30 mcg/hr for over one week.
The effect of the volume %, Φ, of drug composition depots on the release rate of drug was illustrated by making two sets of devices identical in all respects except in the volume % of the depots. One set met relationship 1 above, the other did not.
The devices of both sets consisted of the copolymer of Example 12 and pilocarpine nitrate having a specific surface area of 1.3 m2 /g (d=3.4 microns). In the set meeting relationship 1, the volume % of pilocarpine was 22.9, in the other it was 36.2. The release rates of pilocarpine nitrate from these devices were determined by the procedure of Example 12, part (b). These rates, in mcg/hr, are plotted against time in FIG. 16, with the squares representing data for the devices meeting relationship 1 and the circles representing data for the other set. As shown in FIG. 16 after an initial 22 hr period of nonsteady state release the devices meeting relationship 1 exhibited an essentially constant release rate of approximately 30 mcg/hr. The other devices exhibited a release rate approximately proportional to time-1/2.
The effect of depot size, d, on the release rate of drug was illustrated by making two sets of devices identical in all respects except in depot size. One set met relationship 1 above, the other did not.
The devices of both sets consisted of 73 v% of the copolymer of Example 12 and 27 v% pilocarpine nitrate. In the one meeting relationship 1 the pilocarpine nitrate had a specific surface area of 1.3 m2 /g (d=3.4 microns). In the other the pilocarpine nitrate had a specific surface area of 3.6 m2 /g (d=1.2 microns). The release rates of pilocarpine nitrate from these devices were determined by the procedure of Example 12, part (b). These rates, in mcg/hr, are plotted against time in hr in FIG. 17, with the squares representing data for the set meeting relationship 1 and the circles representing data for the other set. As shown in FIG. 17 after an initial 24 hr period of nonsteady state, high pilocarpine nitrate release the devices meeting relationship 1 exhibited an essentially constant release rate of approximately 40 mcg/hr. In contrast the other set of devices exhibited a release rate approximately proportional to time-1/2.
Modifications of the above described osmotic bursting drug delivery devices that are obvious to those of skill in the chemical, polymer, pharmaceutical, or medical arts are intended to be within the scope of the following claims.


text:
President Xi Jinping Witnesses Signing Ceremony of Agreement on Establishing Confucius Institute at National University of Cordoba in Argentina
At around 12 a.m. on December 2nd, local time, Chinese President Xi Jinping, during his state visit to Argentina after the 13th G20 Summit, attended the signing ceremony of a series of cooperation agreements between the two countries with Argentine President Mauricio Macri. They together witnessed the signing of the agreement on establishing the Confucius Institute at the National University of Cordoba.
Located in South America, Argentina has a population of 40.11 million and an area of 2.78 million square kilometers. Its official language is Spanish, and its education level ranks high among all Latin American countries. The National University of Cordoba, founded in 1613, is the oldest university in Argentina. There are 130,000 students, more than 9,000 teachers and 3,000 researchers. In recent years, with the growing demand for Chinese learning in Argentina, the university has been actively engaging in Chinese teaching. At present, more than 300 students are learning Chinese at the university. In order to promote more formal Chinese teaching, the university has reached consensus with Hanban on co-establishing the Confucius Institute.
The establishment of the Confucius Institute at the National University of Cordoba is conducive to enhancing Chinese language teaching in the region of Cordoba and even in Argentina at large, and to promoting people-to-people and cultural exchanges between the two nations and the friendship between the two peoples.


text:
Latest Moto G6 leak reveals new color options
Slash Gear02.24.2018Tech & Science
We've known for a while now that an update to Moto G line is on its way, and with this year's Mobile World Congress about to begin it seems Motorola is about to debut its latest. An alleged product image has been leaked, showing the finalized design of the new Moto G6 Plus and highlighting its five different color options. … Continue reading


text:
Edward Sanchez, Director of Engagement at Selerix, weighs in with insight surrounding the challenge of accurately defining and measuring employee engagement. Searching for the right employee engagement solution? Selerix can help. Available Q1 of 2020, Selerix Engage provides a 2-way communication experience that enables organizations to connect with their employees through targeted, relevant communication and… Read more »
Our Blog
Selerix Systems to Debut Selerix Engage at The HRSouthwest Conference™
MCKINNEY, Texas, Oct. 21, 2019 /PRNewswire/ — Selerix Systems, technology and services to conquer the chaos of benefits administration, today announced participation in Texas' premier event for human resource professionals, The HRSouthwest Conference™ in Fort Worth, Texas, Oct. 27–30, 2019, at the Fort Worth Convention Center. HRSouthwest Conference attendees will be able to preview Selerix Engage, the newest product from Selerix that lets… Read more »
Selerix Engage Coming Q1 of 2020!
Workplace communications remain the fundamental, yet often mystifying ingredient in making or breaking the greater employee experience. Increased demands on HR departments often inhibit the creation and execution of strategic, targeted employee communications. The result? A disengaged workforce that can devastate your organization's bottom line. Selerix is excited to announce the Q1 2020 release of… Read more »
What is Employee Engagement? We asked.
Written by: Edward Sanchez, Director – Communications & Engagement Backed by a growing collection of evidence-based research and workplace awareness, it is becoming apparent that the concept of employee engagement is here to stay. Employers are beginning to understand the critical impact that an engaged (or disengaged) workforce can have on an organization's bottom line…. Read more »
2019 HR Florida Observations: Interview With Carolyn Meiners
Another successful HR Florida session in the books! I had a chance to sit with Carolyn Meiners, Sales Director at Selerix, to discuss her observations on the current state of the HR landscape. We discussed employee retention and engagement and why it seems that these two interconnected concepts are so impactful to organizations across the… Read more »
Selerix Systems Announces API Integration With Paylocity
MCKINNEY, Texas, Aug. 23, 2019 /PRNewswire/ — Selerix Systems, a leading provider of employee benefits software, today announced the general availability of real-time API integration with Paylocity. This integration allows groups managing benefits on Selerix's BenSelect system to synchronize continuously with the payroll system, replacing the typical file-based data exchange process. "API integration has many important advantages over the periodic… Read more »
ACA Penalty Letters Lost in the Mailroom?
30,000 notices. $4.4 billion dollars in penalty assessments. Misplaced or lost penalty notices from the IRS can be devastating. A cautionary tale worth reading.
ACA Reporting: Technology is Only Half the Equation
2019 ACA Reporting comes with a lot of issues. Don't let technology be one of them.


text:
Published on
Do you want to create a cross-platform game and you don't want to die developing for different native platforms? In this session you will learn how to build a successful game that runs on any device taking advantage of the cross-platform capabilities of HTML 5. GameDuell's HTML5 Game Architect Josep Prat will deliver a bottom-up journey from the backend strategies backed up by Java, to the architectural design of the HTML 5 client. Starting by defining what is true cross-platform architecture he will proceed to discuss the available technologies and their advantages and restrictions. From websockets, over long polling, CSS 3 transformations to protocols different aspects of an efficient and lean development process will be introduced by him. Josep will also explain how to structure a cross-platform project in the correct layers and conclude his talk with a live demo of a GameDuell prototype to showcase an efficient approach for a hands-on usage in efficient development projects.


text: Nice in Angola doing Trampling, live only on ABIME-ET-CANYON.COM. To fuck baby is very simple. Just send a message. Today in this city the most popular girl - Old Anetta. Cross dressed in the undergarments of the opposite sex for a sexual purpose in the presence of 1 or more other people. given oral sex.


text:
Yesterday, thousands of pages were unsealed, and today, Epstein is dead? Well … Epstein's death won't prevent those docs from going public. All the people who helped Epstein to commit crimes are well and alive.
Yesterday, we learned that former gov. of New Mexico and Clinton's cabinet member was allegedly involved into it but, of course, he denied it right away. I believe the point of no return has been crossed. Names of the rich and powerful will be out.
WASHINGTON, DC – MAY 05: Former Governor of New Mexico Bill Richardson attends at the Conference on Iran on May 5, 2018, in Washington, DC. Over one thousand delegates from representing Iranian communities from forty states attend the Iran Freedom Convention for Human Rights and Democracy. (Photo by Tasos Katopodis/Getty Images)
That's right anon, the names are out, and we need a lawyer to answer an NDA question. The victims won a civil lawsuit last year, and they had to sign NDA, now that Epstein is dead is the NDA still enforce? If it's not that's a lot of victims that could come forward and testify against these scum bags. We know it's not just a few, but many partaking in this sic shit.
They need to round up Ghislaine Maxwell now before she starts taking a dirt nap!
Let the scum party this weekend. It might be their last one. No ones above the law! Right, Killary?
thank you anon, God bless America 🌸😎🙏🏼


text:
Congressional Record
Proceedings, Debates of the U.S. Congress
December 16, 2014
113th Congress, 2nd Session
Issue: Vol. 160, No. 155 — Daily Edition
Entire Issue (PDF)
CLOTURE MOTION; Congressional Record Vol. 160, No. 155
(Senate - December 16, 2014)
Text available as:
Formatting necessary for an accurate reading of this text may be shown by tags (e.g., <DELETED> or <BOLD>) or may be missing from this TXT display. For complete and accurate display of this text, see the PDF.
[Pages S6870-S6872] From the Congressional Record Online through the Government Publishing Office [www.gpo.gov] CLOTURE MOTION The PRESIDING OFFICER. Under the previous order, there is 3 hours of debate equally divided in the usual form on the motion to invoke cloture on the Saldana nomination. Mr. REID. Mr. President, I suggest the absence of a quorum. The PRESIDING OFFICER. The clerk will call the roll. The assistant legislative clerk proceeded to call the roll. Mr. REID. Mr. President, I ask unanimous consent that the order for the quorum call be rescinded. The PRESIDING OFFICER. Without objection, it is so ordered. Mr. REID. Mr. President, it would probably be appropriate that I suggest the absence of a quorum but ask unanimous consent that the time be divided equally. The PRESIDING OFFICER. Without objection, it is so ordered. Mr. REID. This would be during all quorum calls today--because there will be several of them--that the time be divided equally on the Saldana matter. The PRESIDING OFFICER. Without objection, it is so ordered. Mr. REID. Mr. President, I suggest the absence of a quorum. The PRESIDING OFFICER. The clerk will call the roll. The assistant legislative clerk proceeded to call the roll. Mr. CORNYN. I ask unanimous consent that the order for the quorum call be rescinded. The PRESIDING OFFICER. Without objection, it is so ordered. Mr. CORNYN. Mr. President, more than 3 months ago I was proud to introduce a fellow Texan, Sarah Saldana, to the Homeland Security and Governmental Affairs Committee in connection with her nomination to become the Nation's top immigration enforcement official, a position important to our country and particularly to Texas. Ms. Saldana was born in Corpus Christi, TX, and became the first Latina U.S. attorney in Texas history and only the second woman to hold that position in the 135-year history of Texas, in the northern district, a region that includes the Dallas-Fort Worth metroplex, spans 100 counties, and stretches across 95,000 square miles. I, along with former Senator Kay Bailey Hutchison, was proud to support her nomination to that important job. In her role as U.S. attorney and previously as a line prosecutor, Sarah Saldana has fought public corruption. She has fought organized crime, sex traffickers and other dangerous criminals. She has also prosecuted numerous high-profile public corruption cases, including the very publicized corruption trial that resulted in the conviction of the former Dallas mayor pro tem, Don Hill, and the ongoing case against Dallas county commissioner John Wiley Price--both members of her political party--which put her in some disfavor, as you might imagine, in Democratic political circles. But it was something which demonstrated to me that she was a person of courage and conviction and she believed in enforcing the law beyond purely deferring to personal political interests. Throughout her career she has developed an outstanding reputation, and based on her qualifications alone, we would be hard-pressed to find a person better suited for the job at Immigration and Customs Enforcement than Sarah Saldana. Unfortunately, the President changed everything this last November by his Executive action on immigration. To be clear--I have said this before on the floor, but I will just repeat--I believe the President's actions are beyond his constitutional authority and are a reckless political stunt. Here are the sorts of things the President is claiming to do. The Department of Homeland Security has issued a series of directives pursuant to the President's instructions on November 21, doing everything from repealing the Secure Communities Program, by which local law enforcement cooperates with Immigration and Customs Enforcement and when a person is arrested who also is in the country illegally, they are detained by local law enforcement, even though they have served their time or otherwise are subject to release so that ICE can come pick them up and return them to their country of origin. The President's Executive action and the Department of Homeland Security directives pursuant to that eliminate the Secure Communities Program. It also purports to prioritize immigration enforcement according to three priorities. The problem is these add even more confusion to what is already an indecipherable and confusing mess, and it also puts to the lowest priority people who have been convicted of crimes such as child abuse, stalking, theft, some child pornography offenses, possession, distribution of alcohol to minors, hit-and-run, including some hate crimes, property destruction, false imprisonment, some abduction offenses and the like. In other words, the President's priorities for immigration enforcement really represent a wholesale [[Page S6871]] change in the law--if they were actually authorized. Until they are set aside by a court or if Congress were to repeal them along with what would require a Presidential signature, they are the standing requirement for any Director of Immigration and Customs Enforcement. The President, purportedly, also used his authority to issue work permits for millions of people illegally in the country. While I don't believe our country would ever engage in mass deportation, the fact that the President has usurped the authority of Congress and purports to take on the authority to issue work permits to people illegally in the country to me is mind boggling. This is the situation into which the President has put a good and decent person such as Sarah Saldana. The President has put the next Director of Immigration and Customs Enforcement in an untenable position. When confirmed, she will be the principal enforcer of our immigration laws. Unfortunately, she now claims the President was operating within his legal authority to issue this Executive action. I say that because several Senators on the Senate Judiciary Committee issued written questions to the nominee about this Executive action, and it is clear in her responses that Ms. Saldana has wholeheartedly embraced the President's Executive action and claims that it is within his authority. If you think about it, a Presidential nominee has two choices. They can either say, well, I disagree with what the President has done, so I will refuse to serve, or if they are already confirmed, I am going to resign my position, or they can embrace the President's policies, because the President is the one who makes those policies. Clearly, Ms. Saldana has embraced the President's policies, which I believe are unconstitutional. I believe we should be deeply concerned about the damage the President's Executive actions will do to our already broken immigration system because they reinforce the dangerous message that the President is already sending to the world that our laws against illegal immigration will not be enforced. This is an invitation for lawlessness, and it will make it much more likely that we will experience further humanitarian crises and a surge of illegal immigration such as we saw last spring and which we have seen this year with more than 60,000 unaccompanied children coming from Central America through Mexico to our southern border. So the President's policies are a green light, and, unfortunately, Ms. Saldana has embraced those policies. I believe that the recent election was a mandate for us to work together on bipartisan solutions to our country's biggest challenges, but apparently the President didn't get the memo. I was actually at a lunch at the White House with other leaders of both parties across the Capitol where Speaker Boehner, the incoming majority leader and I, and the current majority leader said to the President: Please don't do this. Don't poison the well. Give us a chance to do our job as the new majority in the House and the Senate to try to pass consensus immigration reform bills and put them on your desk. The President ignored that. So the President chose to poison the well and to make it harder for us to do what we know we all have to do; and that is to fix our broken immigration system to the best of our ability. The President's reckless Executive actions have done further damage. They are deeply unfair to people who have been waiting patiently in line according to the written immigration laws--the people who have been playing by the rules. To allow millions of people simply to jump ahead of those people who have been waiting patiently in line and playing by the rules is profoundly unfair. At a time when our economy is starting to recover from the financial crisis in 2008 and the policies that have intervened, we know that there is potential harm to hard-working middle class families who are already living on stagnant wages and a rising cost of living to have millions more people eligible for work permits under the President's purported authority in these Executive actions. We ought to be careful about that, we ought to be deliberative about that, and we ought to make sure we are doing the sorts of things that will protect--not harm--hard-working middle class families. But the President has ignored all that and just done it his way. Well, some pundits have suggested perhaps the President's real goal was to provoke Republicans to taking the bait and descending into further dysfunction. Well, if I heard one message from my constituents and people as I campaigned for reelection in Texas, it is that people really want us to work together. They want this place to function. In many instances they don't care so much about what we do, as long as we do something to work together. Of course, they care about what we do, and there are areas where we disagree. But there are areas of common ground where we can work together to solve these problems. We are not going to take the bait if that is what the President's intention was, and we are not going to descend into even more dysfunction. That would be a repudiation of the message and mandate the voters sent to us on November 4. So we are going to plow ahead. When the new majority takes place on January 6, working with our colleagues in the House, working with our colleagues across the aisle, we are going to try to find places where we can pass bipartisan immigration legislation--not in a comprehensive fashion but in a step-by-step fashion to try to make some progress to improve our broken immigration system. I am most concerned about the precedent the President's actions would set for our system of government. What if future Presidents take upon themselves the claimed authority to issue other Executive actions that ignore the separation of powers and allocation of responsibilities given to the different branches of government under our Constitution? It is a dangerous precedent. If the President cannot be trusted to enforce the laws passed by the people's elected representatives, then self-governance is an illusion. This is very dangerous. The American people should never stand for rule by Executive fiat, and they should demand the rule of law be enforced under our Constitution. The President's frustration with the Republican House of Representatives is no justification for doing what he has done. He needs to give us an opportunity to do our job, and he needs to join us at the negotiating table to make progress on our broken immigration system. Although I admire Ms. Saldana, I fear she will be tasked with carrying out the implementation of the President's unconstitutional Executive actions, refusing to enforce our immigration laws. Unfortunately, when given the chance to address the constitutionality of these actions with the Judiciary Committee, these fears were not alleviated. Members of the committee were denied a chance to ask her questions during an open confirmation hearing, something several previous nominees for this position have undergone. As a matter of fact, Senator Grassley, the ranking Republican on the Judiciary Committee, and I invited Ms. Saldana to appear at an informal question-and-answer session, since the chairman of the Judiciary Committee denied us an opportunity to have a formal hearing, so she could perhaps answer our questions and clarify her position--the position she took in the written answers to the questions for the record, which I referred to earlier. I don't know whether she got bad advice or whether she, herself, decided it would be a futile effort, but she decided not to appear for that informal give-and-take. Maybe it would have helped her clarify her answers to the questions sent by the committee, maybe not. Maybe she would have stood by her answers, but we will never know. It is for these reasons I regrettably cannot support her nomination. Ms. Saldana, as I said, is somebody whom I admire and respect, but if she is determined to help the President implement this deeply flawed Executive action and refuses to enforce the law Congress has written and has been signed by previous Presidents, I cannot support her nomination. I will not aid and abet a President dead set on unilaterally defying our Nation's immigration laws. I yield the floor. The PRESIDING OFFICER. The Senator from Illinois. [[Page S6872]] ____________________