QDIS Blog

Implantable drugs are something I have spent quite a bit of time thinking about for a couple of reasons. This article on the recent approval of Implanon contraceptive (which lasts three years) from Organon got me thinking again.

FDA approves implantable contraceptive - Yahoo! News:

A little background: this of course is not the first implantable contraceptive. Wyeth (formerly American Home Products) had Norplant approved back in 1990 which they stopped selling in 2000 after several lawsuits. Norplant lasted seven years and was implanted in the forearm. Since then, there haven’t been any implantable birth control. Another implantable drug is the Gliadel wafer for brian cancer. This is implanted near a tumor in the brain and was approved in Feb 2003. There may be others but my point is the technology exists and could be used in other areas.

Back to my thoughts on implantable drugs. I spent about five years working on a polymer drug conjugate which, although not implantable (it was delivered by IV) had a lot of similarities to polymer rug released products. I spent a lot of time learning about analytical methods for characterizing polymers in a cGMP environment.

I have also had some experience with schizophrenia; I had my best friend with schizophrenia in graduate school commit suicide by taking potassium cyanide from the chemistry stockroom. I also know a little bit about how depression and other mental illness and their effect people and there families. One of the problems with these sorts of medical problems is that once these people are on the correct drug, their symptoms disappear and they feel much better. In fact, it is not uncommon or them to feel so good, they think they no longer need their drugs. Another problem is CNS drugs have undesirable side effects ranging from headaches, to feeling like your thinking is slow, to sexual problems, and others issues. So there are several reasons people want to go off their medications even though it may indeed be helping.

My though has been to make implantable forms of CNS drugs. Now, I’m the first to admit that there are potential problems with this. What if there are serious side effects? One of the problems with Norplant was not that it didn’t work but that there were complications with trying to get the implant removed and there were also some side effects. My thought was to put patients on an oral form of the drug to see if there are any side effects and then if there are not, the implantable form could be used. This would be especially useful in serious cases of schizophrenia in patients who may be a danger to themselves or others. This would solve the “roller coaster” problem of going on and off drugs causing even more problems. I would say that I also realize that this would not be appropriate in all circumstances and would have to be managed carefully at first. However, the long term pay off should be more than worth it in preventing re-occuring hospitalization of those with serious problems.

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QD Information Services now offers custom experimental designs. No matter what your need, QDIS can develop an experimental design to suit your needs. These designs are computer generated and are setup in order to give you the greatest confidence in the results results. DOE gives you the ability to know for sure if you are it the optimal settings for your process.

What is Design of Experiments (DOE)?

Design of Experiments is the use of a carefully selected group of experiments chosen to give the most information with the fewest number of experiments. While not well know, the technique has been around for many years. It is just now becoming popular as is a great tool for optimizing any process. If you need to maximize or minimize some measurement then DOE can help you. Not only do you get the most information from the fewest experiments, but you also generate a model which allows you to predict results at other areas within your experimental space.

What Can Design of Experiments Do for You?

• Optimize any process
• Optimize the yield of a chemical reaction
• Minimize the amount of an impurity
• Allows you to show that you understand and have a chemical process in control
• Gives you an indication of what further experiments may be needed

Contact QD Information Services for a free quote for an experimental design for your specific needs. Since each situation is unique, the pricing depends on your exact needs.

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I want to talk about a couple of alternative solvents that get overlooked quite a bit in organic synthesis. The first is diethoxymethane (DEM; CAS [462-95-3]).

It has several uses based on it’s properties. First, it is a very good solvent fr Grignards and other organometallic reactions due to its low water levels typically less than 150 ppm (water solubility in DEM is 1.3% w/w). It llso has limited solubility in water; 4.2% w/w. It also has a low boiling ponit (88 °C) and Another attractive property is that DEM azetropes with ethanol (bp 74 °C, 58% DEM) and with water (bp 75 °C, 90% DEM).

It does tend to form peroxides after being opened and it is flammable (flashpoint of -5 °C). It is stable to base but does decompose under strong acid conditions.

While the solvent has been known for some time, it has only in the past ~6 years been commercially available in large quantities (55 gal drum to railroad tankcars from Eastman). It is in general a good replacement for dichloromethane, tetrahydrofuran, glyme (1,2-dimethoxyethane), and methylal (1,1-dimethoxymethane).

Here’s some information from Eastman Chemical and a publication from a few years ago in Org. Process Res. and Dev. 2001, 5, 127.

Eastman Chemical Information

Applications of Diethoxymethane as a Versatile Process Solvent and Unique Reagent in Organic Synthesis

Another solvent that gets overlooked is 1,3-dimethyl-2-imidazolidone (DMEU or DMI; CAS [80-73-9]). This can be used as a replacement for the highly toxic HMPA as a dipolar aprotic solvent.

It is very similar to 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone [7226-23-5] but has a lower boiling point.

It is similar to dimthylformamide but tends to be more stable. It is stable to alkali metals and strong bases and has a boiling point of 225 °C. Mitsui Chemicals America has a nice site with information on 1,3-dimethyl-2-imidazolidone including physical properties, chemical properties and some applications.

I have used both of these in my past and have been happy with the results and hope others will consider them for future projects.

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Since I personally suffer severely from post-operative vomiting and nausea I was especially interested in Merck’s new approval for Emend. This is the first new treatment for this in over 10 years.

Merck Gets Added FDA OK for Emend: Financial News - Yahoo! Finance

I have only had surgery twice; once for a knee injury and the second for a deviated septum in my nose. Both times, I was very sick afterwards and could not keep down even water for about 48 hours. I was told the first time it was due to some carrier gases they used in the anesthesia (this was back in 1978) and more recently after the nose surgery it was said to be due to the fentanyl pain reliever. It’s nice to know this and I’ll certainly keep it in mind if I ever have to have electively surgery again.

I should mention that this is also used for nausea caused by chemotherapy.

Here’s some more information on Emend.

EMEND* (aprepitant) is a substance P/neurokinin 1 (NK1) receptor antagonist, chemically described as 5-[[(2R,3S)-2-[(1R)-1-[3,5-bis (trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)-4-morpholinyl]methyl]-1,2-dihydro-3H-1,2,4-triazol-3-one.
Its empirical formula is C23H21F7N4O3, and its structural formula is:

Other Sources

• Chemotherapy side effects information at emend.com
• Contract Pharma - FDA Approves Merck’s Emend
• FDA approves Merck postoperative nausea drug

Technorati Tags: Merck, Emend, nausea

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Somehow I missed when it was originally announced that a new once-a-day HIV combination has been approved by the FDA. But Mark over at Eye On FDA has a great post about just how important this is.

Eye on FDA: A Win for the FDA and for 3 Companies - Gilead, BMS and Merck

This is indeed a major breakthrough and should change how AIDS is treated world-wide. It makes it much easier to get compliance from people on the drugs. One of the problems in developing countries is trying to get patients to stick to a strict schedule of when the various drug cocktails need to be taken and not sticking to it can lead to development of drug resistant virus.

For those interested, here is the chemical structure for the three drug combo.

Efavirenz: Efavirenz is chemically described as (S)-6-chloro-4-(cyclopropylethynyl)-
1,4-dihydro-4-(trifluoromethyl)-2H-3,1-benzoxazin-2-one. Its molecular formula is
C14H9ClF3NO2 and its structural formula is:

Efavirenz is a white to slightly pink crystalline powder with a molecular mass of 315.68.
It is practically insoluble in water (<10 μg/mL).

Emtricitabine: The chemical name of emtricitabine is 5-fluoro-1-(2R,5S)-[2-
(hydroxymethyl)-1,3-oxathiolan-5-yl]cytosine. Emtricitabine is the (-) enantiomer of a
thio analog of cytidine, which differs from other cytidine analogs in that it has a fluorine
in the 5-position.
It has a molecular formula of C8H10FN3O3S and a molecular weight of 247.24. It has the
following structural formula:

Emtricitabine is a white to off-white crystalline powder with a solubility of approximately
112 mg/mL in water at 25 °C.

Tenofovir disoproxil fumarate: Tenofovir DF is a fumaric acid salt of the bis-
isopropoxycarbonyloxymethyl ester derivative of tenofovir. The chemical name of
tenofovir disoproxil fumarate is 9-[(R)-2[[bis[[(isopropoxycarbonyl)oxy]-
methoxy]phosphinyl]methoxy]propyl]adenine fumarate (1:1). It has a molecular formula
of C19H30N5O10P • C4H4O4 and a molecular weight of 635.52. It has the following
structural formula:

Tenofovir DF is a white to off-white crystalline powder with a solubility of 13.4 mg/mL in
water at 25 °C.

Further information

• BMS press release on Atripla
• Gilead — U.S. Food and Drug Administration (FDA) Approves ATRIPLA(TM) (efavirenz 600 mg/ emtricitabine 200 mg/ tenofovir disoproxil fumarate 300 mg), The First Once-Daily Single Tablet Regimen for Adults with HIV-1 Infection
• Full prescribing information from Gilead (pdf)
• CNN.com - Single-dose ‘cocktail’ OK’d for U.S. HIV patients - Jul 12, 2006

Blog posting about Atripla

• DOCFILES: Atripla : Once daily tablet for treatment of HIV1
• The J Train: Atripla
• The Biotech Weblog: FDA Approves Atripla, Once Daily Single Tablet AIDS Drug

Technorati Tags: FDA, HIV drugs, Atripla

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The LA Times (and some other newspapers) had an article on recent action by the US Senate easing drug imports for personal use.

Senate Votes to Ease Drug Imports - Los Angeles Times

The US House passed similar legislation earlier this year. It basically says that US Custom officials can not seize drugs imported from Canada for personal use. It should be pointed out that this does not become law until the House and Senate work out differences. The key is that the Senate version only specifies Canada and the House version would allow imports from any country (this I do think brings about a safety concern).

Now I’m not a big fan of importing drugs for a couple of reasons. First, it merely treats a symptom instead of addressing the underlying cause. There is no way Canada can supply even a minor part of the drugs needed for US consumers! The population of Canada is ~33 million as of July 2005 and the US will reach 300 million people sometime this year. This means that the US population is almost ten times as large as Canada. If we assume that the percentage of people using pharmaceuticals is similar then even if the US bought all the drugs in Canada, only 10% of those in the US could get their drugs from Canada. THis is hardly a solution.

Also, there is talk (and it may already be happening) that pharmaceutical companies will limit the amount of a given drug that a given pharmacy can order in a given time period. If they chose to sell it into the US instead of providing it to their own people, that is there choice. Canada has also stated they may limit the exporting of drugs from Canada into the US.

CBC News: Canada to allow bans on bulk drug exports (29 June 2005)

While it doesn’t say Canada will limit exports it does indicate they could at any time.

I also have argued that this is in effect allows price controls. In Canada and most other countries in the world the government purchases the drugs at set price which is price controls. By allowing imports from Canada, our government is basically saying they agree with price control since that is how Canada prices their drugs. Although the Republicans have been against allowing drug imports citing safety concerns, I think it will indeed pass because it is an election year and this is a topic that effects seniors and most seniors vote!

Concerning the safety concern that are often brought up: I think this is something that could indeed be worked out but it would need to include a list of countries from which people could import drugs. Opening it to all countries is a mistake in my opinion. I don’t have all the answers but getting prescription drugs from Canada is at best a very short term patch to a more complicated situation.

Other Resources: (note all of these are basically the same)

• Senate Backs Allowing Drugs From Canada: New York Times
• Senate OK’s Canadian drug import plan: Boston Globe
• Senate OKs drug imports from Canada: Seattle Times
• Senate OKs Import Prescription Drug Plan: Forbes

Google News results for this.

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The first sentence of this article caught my eye.

What if you organized an important cancer clinical trial and nobody came? That scenario could become a reality for oncology researchers across the United States, new research shows.

Clinical Trials for Cancer Running Out of Volunteers - Yahoo! News:

The article goes on to say that in order to complete all of the 679 trials at all phases for lung, breast and prostate cancer you would need 238,000 patients. That corresponds to half of all cancer incidences. This means that at least half of people diagnosed with cancer would need to participate in a clinical trial and note that the 238,000 needed only covers breast, lung, and prostate cancer!

I don’t dispute the numbers and based on my experience this is pretty close to true. However, It should be noted that they picked the three types of cancer that have the largest number of trials currently. I do know from a project I was involved in for non-small cell lung cancer it was deemed impossible to get enough patients in the US and western Europe in the required timeframe. Therefore, the trial ended up recruiting world-wide in South America, India and eastern Europe.

Cancer trials tend to be the current trend for a couple of reasons. One, there are some types of cancer that meet the unmet medical need as defined by the FDA and drugs to treat these are given special consideration. A lot of this came about from the AIDS activism in the 80’s. Also, cancer tends to be a highly profitable area for drugs. I’ve not seen recent numbers for drug sales broken down by therapeutic area but I’m sure oncology is high on the list.

The question is what, if anything needs to be done. I tend to think that the numbers aren’t as bleak as it has ben made out to be.
One thing is better education of oncology doctor as to what is available, especially for patients who don’t respond otherwise. Let’s hope this isn’t a trend and merely a momentary decline.

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Roche is continuing to add additional manufacturers for Tamiflu just in case. The latest addition is Cardinal Health as reported in Yahoo News.

Cardinal Health Signs Roche Tamiflu Pact: Financial News - Yahoo!

And here is the press release from Cardinal Health.

Cardinal Health will make Tamiflu in Europe and has the ability to print packaging and printed inserts in the US. It appears they will only be producing the 75 mg hard gelatin capsules.

I think this is a smart decision on Roche’s part which allows them to increase production without major capital investment on their part. It would be interesting to know how the terms of the contract and what exit clauses there may be for Roche in case the need never arises. Either that or they may just have them do a certain volume regardless. Either way, I think this is a great way to ensure a supply if needed without having to make large investments that wouldn’t be available for several years.

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I’ve read many articles recently about attempts to improve the whole drug development process and much of the focus seems to be on the drug discovery side. While I agree that drug discovery can be made more efficient, I think that this may just result in moving the bottleneck to the development arena, an area that in general from my experience gets somewhat overlooked in terms of how do we make development (making clinical trial materials) more efficient. I do think that the decoding of the human genome will eventually result in more potential target for drug discovery and help to focus their efforts in the future since most of the low lying fruit has already been picked. I think many people were overly optimistic as to how long it would be before the decoding of the human genome would lead to something concrete.

A large part of the problem is you don’t want to spend an inordinate amount of effort developing a great route to a compound, only to have it fail in the clinic. Determining failure in the clinic as soon as possible is imperative before they get into the large and expensive phase III trials. However, by the time it is clear that the drug will indeed succeed, it is usually determined (mainly by management and regulatory departments) to be too lately to make any changes to the route. This invariably leads to an inefficient processes being rolled out commercially. One of the reasons for that is the amount of work required to change a commercial route once it is validated and filed. I truly think more effort needs to be dedicated to getting a workable process in place for making changes to allow for

Process analytical technology (PAT) will help if it can be economically done by retrofitting current facilities. Expecting companies to scrap investment in facilities and equipment just to incorporate PAT is unlikely to happen. However, if PAT could be easily retrofitted into existing equipment it would certainly be more widely adopted.

Note that the bulk active post approval changes guidance has been removed from the FDA Guidance website since it was reported in the Federal Register on June 1, 2006 that they were “inconsistent with the agency’s initiative, Pharmaceutical Current Good Manufacturing Practices (CGMPs) for the 21st Century (CGMP Initiative). However, looking through the CGMP Initiative nothing directly addresses the issue of what needs to be done if a change is to occur after approval. I for one sincerely hope this is an area of development that is looked at in more detail to allow for changes to occur which could improve the quality and efficiency of producing bulk active ingredients.

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I am always interested in new resources related to chemistry on the Internet. I am always looking for quick way to do structure searching since the commercial databases that offer this tends to be quite expensive. There are a couple that I’m sure most people are familiar with such as Chemfinder from Cambridgesoft or ChemIDplus from the NIH.

A newer one (or at least it’s new to me) is Chembank from Harvard. They have a fairly sizable database (over 466 thousand compounds). There is a variety of way to search but I found the substructure search to be easy to use and fairly quick. It gives you a nice Java based molecular editor to draw your substructure.

Here is a sample results for a search I performed.

You can also export the result in either tab delimited text or as an sdf file.

Clicking on a compound gives you detailed information.

My only compliant is that it doesn’t list which libraries these compounds come from. It merely states they are from vendor libraries and FDA approved drugs. It would be nice to know more about which libraries are included and if the database is going to continually updated.

While it isn’t as large as commercial databases, Chembank is a good place to go if you need to do some structure searching.

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