Last week we addressed a contemporary issue involving Clinical Pharmaceutics. That issue centered on the proper dosage form for a neonate that also involved the solubility of the drug and the form in which it was to be administered as required by a PBM due to their unwillingness to pay for a proper compounded prescription. This week, we will look at the change in an excipient back in the late 1960s that lead to an outbreak of phenytoin intoxication in Australia, also related to solubilities.

Upon investigation of the situation in Australia, the contents of the phenytoin capsules in question were analyzed and found to be okay (i.e., they were not overfilled with the drug); therefore, there must have been some other reason for the toxicity. It was determined that the affected patients all received one brand of 100-mg phenytoin sodium capsules. During the inquiries, it was discovered that the manufacturer had changed the diluent from calcium sulfate to lactose along with a slight increase in the contents of both magnesium silicate and magnesium stearate in the capsules.

Calcium sulfate is only listed as "slightly soluble in water," whereas lactose is "freely soluble in water." This increased solubility of the diluent can serve to more rapidly "wet" the phenytoin sodium (freely soluble in water) powder particles and "wetting" is the first step in the dissolution process; the enhanced wetting with lactose led to more rapid dissolution of the phenytoin sodium as compared to when calcium sulfate was used. Both substances are listed as "diluents" but their solubility properties are different. Upon changing back to the previous formula using calcium sulfate, the blood levels of the patients returned to previous values.

From this experience, it became apparent to manufacturers back in the 60s that excipients are not "inert" substances and must be carefully evaluated for their effect on the drug dosage form.

Loyd V. Allen, Jr., PhD, RPh
Editor-in-Chief
International Journal of Pharmaceutical Compounding
Remington: The Science and Practice of Pharmacy Twenty-second edition

News

"Great British Drugstore" to Sell Prescription Medicines in Maine
A United Kingdom (UK) pharmacy is about to take advantage of a law that allows Maine residents to purchase prescription drugs from some foreign pharmacies. The arrival of the Great British Drugstore may further the debate over importing drugs from overseas. Maine residents can purchase their prescription drugs through a broker from pharmacies that are licensed in Canada, the UK, New Zealand, and Australia.

Already, two Canadian online brokers began offering services to Maine residents; now there is the emergence of a pharmacy from yet another country.

How it works: Maine residents can purchase medicines online, although the Great British Drugstore plans to process prescriptions from an office in Portland. The pharmacy has 61 locations in the UK as well as a website; it does not have to be licensed in Maine under the state law. The medications will be supplied by UK wholesalers that receive product directly from manufacturers. The FDA prohibits importing medication except for personal use if the drug is not misbranded or unapproved.
http://blogs.wsj.com/pharmalot/2014/10/08/in-maine-the-british-are-coming-to-sell-prescription-medicines-online/#

ASHP Requests Genentech to Reconsider Limited Distribution Scheme
Genentech is putting in place a limited distribution program using specialty pharmacies for bevacizumab, trastuzumab, and rituximab that could adversely impact patient care. ASHP's CEO, Paul W. Abramowitz, recently requested that the manufacturer place a moratorium on the change and convene a group of stakeholders to consider the ramifications of their limited distribution scheme on patient care and the pharmaceutical supply chain.

US Docs Question High-Priced Drugs?
On the JAMA website, Dr. Peter B. Bach of the Health Outcomes Research Group at the Memorial Sloan-Kettering Cancer Center writes that some in his community are worried that the high prices of some drugs are not properly linked to their benefits and value.

The tricky part is that "benefit" and "value" will be like beauty (it's in the eye of the beholder). The paper says that in 2013, spending on specialty drugs (mostly cancer medicine) totaled $73 billion. He notes that eight new cancer drugs were approved by the FDA in 2013, with the Medicare "price," for those eight new drugs ranging from $7,000 to $12,000 per month; however, some of the drugs showed survival improvement for six months while some showed no improvement. Bach defines "value" as "the benefit of a treatment with respect to its cost."
http://www.philly.com/philly/business/homepage/Can-the-US-control-high-priced-drugs-Pharma-connected-doc-gingerly-walks-up-to-the-issue.html

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Did You Know ...

�that antibiotics are the only drug where use in one patient can impact the effectiveness in another?

Tip of the Week

Consider minimizing the number of "automatic refills" for antibiotics provided to patients if they no longer need the antibiotic.

Looking Back

The blackened forest
Smoulders yet,
Because he flipped
A cigarette!
     Burma Shave