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The Blurred Line Between "Topical" and "Transdermal", Part I
This week, we will look at the "equivalence" issue between different formulations.
With cost considerations and pricing variations between products, it is often assumed by many that the formulations containing the same drug concentrations are generally equivalent. However, there is a great deal of clinical and scientific evidence showing that formulation changes or different manufacturing processes can alter the clinical efficacy of a drug. Showing bioequivalence between formulations, however, is more difficult and complex than the use of AUC numbers like those used from oral and parenteral administration. It seems that vasoactive assays provide some benefit in comparing formulations, however, not all topically applied drugs are vasoactive.
The bioavailability from topically applied formulations is in the order of 1% to 3% of the dose applied. As we will see next week, it is possible to reduce the concentration of a product like hydrocortisone in a cream vehicle to 0.1% and still be able to deliver the same amount of the steroid as from a 1% formulation. To add more confusion to the issue, there also are preparations using different forms of the same drug with different salts or esters. As examples, hydrocortisone is formulated as the free base (1%, mild or low potency), as the acetate (1%, mild potency), and as the butyrate (0.1% [i.e., at one-tenth the free-base concentration] but classed as potent or high potency). To this, add the variability in skin permeability between different body sites and between different individuals that may be in the order of 30% to 40%.
Some in vitro testing methods are applicable for confirming batch-to-batch uniformity during production/preparation but not applicable for bioequivalence testing for those topicals. For drugs that penetrate through the skin and enter the systemic circulation, then plasma levels and Cmax can be determined, but for drugs acting on or within the skin, then biopsies need to be taken to determine drug levels (e.g., punch biopsies for drugs within the stratum corneum, shave biopsy for upper stratum corneum, viable epidermis, and some dermal tissue).
In summary, it is apparent that ensuring equivalence between different formulations of the same drug is not a simple task. A reasonable approach would be that if a specific formulation is working well, maybe it should not be changed.
Next week, we will look at the practice of "dilution of creams and gels."
Loyd V. Allen, Jr., PhD, RPh
Editor-in-Chief
International Journal of Pharmaceutical Compounding
Remington: The Science and Practice of Pharmacy Twenty-second edition
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News
NOTE: If interested, here is the link to the webcast of the FDA Pharmacy Compounding Advisory Committee meeting that took place on February 23 and 24, 2015.
http://www.fda.gov/downloads/AdvisoryCommittees/Committees
MeetingMaterials/Drugs/PharmacyCompoundingAdvisoryCommittee/
UCM434873.pdf
DEA Issues Nationwide Alert on Fentanyl as Threat to Health and Public Safety
The US DEA has issued a nationwide alert about the dangers of fentanyl and fentanyl analogues/compounds; it is commonly laced in heroin, causing significant problems across the country. "Drug incidents and overdoses related to fentanyl are occurring at an alarming rate throughout the United States and represent a significant threat to public health and safety," said DEA Administrator Michele M. Leonhart. "Often laced in heroin, fentanyl and fentanyl analogues produced in illicit clandestine labs are up to 100 times more powerful than morphine and 30-50 times more powerful than heroin." The DEA has also issued warnings to law enforcement that fentanyl can be absorbed through the skin and accidental inhalation of airborne powder can also occur; the DEA is concerned about law enforcement coming in contact with fentanyl on the streets during the course of enforcement.
http://www.dea.gov/divisions/hq/2015/hq031815.shtml
Pharmacies Inside Doctors' Offices
Many consumers seem to favor "one-stop shopping" with their retail choices, so some doctors' offices are starting to adopt the same trend by establishing pharmacies inside their own practices. "It takes a concern away from us of the patient not getting their medication that day," Gainesville Dr. Brent Archer said. "They won't be delayed in their treatment." Patients are given prescriptions and told to have them filled, but what happens is some patients never get them filled. Even though these pharmacies offer one-stop accessibility, hours are limited and the pharmacies don't have the selection of over-the-counter products that are in healthcare retail stores.
http://www.gainesvilletimes.com/section/199/article/108476/
GAO Says DEA and FDA Should Work Together to Solve Many CDS Shortages
The DEA and the FDA should work together more closely to prevent shortages of prescription medications containing controlled substances, said a blistering report from the GAO. The DEA should also improve its process for authorizing quotas of the controlled substances used in these drugs. These shortages can lead to less-effective care, no treatment, and/or medication errors. Providers spend time and resources mitigating the effects of drug shortages instead of taking care of patients.
Pharmaceutical companies charge that the amount of time it takes the DEA to approve controlled-substance quotas is excessive. According to the GAO report, the DEA did not respond to manufacturers' quota applications within the time frames required by the agency's own regulations for any year from 2001 to 2014. The GAO made several recommendations to improve the DEA's management of the quota-application process and to avoid future drug shortages. Among other things, the GAO advised the DEA and the FDA to update their existing memorandum of understanding, which has not been revised since the 1970s.
http://www.medscape.com/viewarticle/841588?src=rss
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