Published in Euro Pharma Exec, Feb. 2005
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Enhancement of transdermal drug delivery with chemicals
To be effective, drugs must reach an intended site in the body, at an effective concentration, and for an appropriate length of time. Transdermal drug-delivery can heighten this effectiveness by avoiding gastro-intestinal distress caused by orally administered drugs, avoiding inactivation of a drug by first-pass metabolism in the liver and gastro-intestinal tract, and can provide local delivery of appropriate concentrations of a drug to the intended site of action without systemic exposure.
SEPA® (Soft Enhancement of Percutaneous Absorption, where “soft” refers to the reversibility of the skin effect) is a family of patented compounds that can enhance transdermal drug delivery by temporarily and reversibly disrupting the alignment of the lipid bilayers within the lipid matrix in the stratum corneum (SC). This disruption renders the skin temporarily permeable, allowing a drug to diffuse through the SC, epidermis, and dermis, where it can enter the bloodstream through the capillaries.
MacroChem Corporation, a Boston area specialty pharmaceutical company, has developed a 9-carbon member of the SEPA family (SEPA 0009, hereafter referred to as SEPA) to enhance topical delivery of a variety of active pharmaceutical ingredients. SEPA has been tested in 48 clinical trials conducted in Europe and the United States involving more than 4,000 human participants either alone or in combination with one of five different pharmaceuticals.
Opterone®, a topical cream containing testosterone and SEPA, is in clinical development to treat male hypogonadism. Topical testosterone delivery solves a number of problems; primary among them, significant first-pass metabolism and risk of liver damage posed by oral delivery, and the pain and inconvenience associated with intramuscular injections. In addition to delivering more testosterone per unit weight of applied dose, the new Opterone cream formulation has also demonstrated the ability to deliver more sustained levels of testosterone over a longer period of time when compared to a first generation gel formulation. It is expected that Opterone’s superior handling quality should better serve the therapeutic needs of hypogonadal men.
EcoNailTM, a lacquer formulation containing econazole and SEPA, is intended as a topical treatment of onychomycosis. Though the condition is not considered serious or life-threatening, it is pervasive, affecting 30 million people in the United States. Only one-quarter of those affected are treated with prescription medication. Current oral prescriptions have an efficacy rate of approximately 40% and patients seeking treatment must be monitored for liver damage. A ciclopirox lacquer with a cure rate of approximately 10% is also available.
An in vitro study using human cadaver nails reported that the presence of SEPA in EcoNail improved delivery of econazole to the ventral aspect of the nail plate in a quantity that exceeded 14,000 times the minimum inhibitory concentration (the amount needed to kill the fungus) for the most common onychomycosis organism1. SEPA enhances econazole delivery through nails by promoting its release from the lacquer matrix. This method of delivering econazole directly to the infection site may circumvent the liver toxicity associated with oral antifungal therapy.
The aforementioned product candidates illustrate the flexibility of the SEPA technology platform. SEPA can be used to enhance local as well as systemic drug delivery. As chemical enhancement technologies mature, more drugs will become candidates for topical delivery in the future.
1. Hui, XY et al. Enhanced econazole penetration into human nail by 2-n-nonyl-1,3-dioxolane. J. Pharm. Sci. 92: 142-148, 2003.
The Shifting Landscape of the Pharmaceutical Industry: How Biotech- Specialty Pharma Hybrids will fill in the gaps
Written by: Crystal Allen for MacroChem Corporation
A Seismic Shift in the pharmaceutical industry is now underway as a variety of market forces converge to form a catalyst for change in the drug delivery sector. While some health-science companies may find themselves at a disadvantage, many others will capitalize on the opportunities presented by these changes. Companies positioned to take full advantage of the shifting landscape are biotechs that can successfully transition to the specialty pharma business model, and traditional specialty pharma companies that are able to incorporate research and development into their business model.
The changes now taking place in the health sciences sector are dramatic and far reaching. Political pressure from congress and consumers is already exerting downward pressure on the price of prescription drugs. Generic drugs will play an increasing role in healthcare as state Medicaid programs begin to enforce lowest-price mandates and managed care organizations encourage doctors to prescribe the least costly formulation of medication.
In the midst of this, patents on blockbuster drugs are expiring in droves, with few drugs in the late-stage pipeline to replace them. In the past two years, 14 well-known drugs with sales totaling 8 billion went off patent. This year patents will expire on 11 drugs with U.S. sales exceeding $18 billion.1 A large number of smaller-market drugs also have, and will continue to have patent protection expire during this period.
These factors have left large pharmaceutical companies scrambling for new products. Up until now, so-called blockbuster drugs have been the backbone of the pharmaceutical industry. But the dwindling supply of blockbusters is forcing some big pharmas to pursue drug candidates that were previously considered too small for their portfolios. In previous years, these drugs were out-licensed to specialty pharmaceutical companies that served various segments of the specialty physician market. As the current market forces take effect, specialty pharmas that have relied on out-licensing in the past, will need to evolve a business model that employs in-house research. Consolidation among this group is inevitable.
Meanwhile, an increasing number of biotechnology companies are seeking to capture the upside value of their products by transitioning to the specialty pharmaceutical business model and bringing the drug formulations they have researched to market themselves, in lieu of licensing them to larger pharmaceutical companies. Biotech companies that have proprietary drug-delivery technology have several advantages when it comes to transitioning to the specialty-pharma model. First of all, they have the ability to give off-patent drugs new life by formulating them with a different drug-delivery system. Another advantage of the drug-delivery approach is the lower risk associated with developing off-patent products, as opposed to new chemical entities (NCEs) which do not have an established record of safety and efficacy as do their off-patent counterparts.
Further, if the clinical advantage offered by the NCE over a previously patented drug is not significant, and the price tag on the NCE is hefty, which is often the case due to R&D costs, the delivery-enhanced off-patent drug is likely to be considerably less expensive, and thus far more attractive to managed care.
The most significant advantage for a company with proprietary drug delivery-based technology is the ability to feed a product pipeline with a virtually endless supply of enhanced off-patent medications made more efficacious with the drug-delivery technology. Companies that have new products that are near the end of their development cycle are in an especially advantageous position since their development risks have been reduced to a minimum, making their products likely candidates to provide significant economic returns.
There are a couple of drawbacks for drug-focused biotechnology companies seeking to cultivate the specialty pharmaceutical business model. One is that drug delivery-improved products must be differentiated for competitive advantage and, simultaneously, cost-effective to get managed care support. Another is that large pharmaceutical companies are now doing drug-delivery conversions of off-patent drugs in-house, a trend that could narrow the options for drug-conversions, and/or create a sharply competitive playing field.
Though today’s pharmaceutical market is a bit slippery, according to industry experts these inconsistencies can be harnessed as development opportunities for those pharmaceutical companies that understand the subtleties of the shifting landscape. Experts like Christopher Meyer (It’s Alive: The Coming Convergence of Information, Biology and Business,) Jack Welch, and others believe today’s unstable market conditions exist across business sectors and will be the norm for the foreseeable future. They believe the companies that survive will be those with business models that accommodate – even capitalize on—market turbulence.
The forces that have led to diminished big pharma demand for drug delivery enhancement of expiring off-patent molecules will continue to threaten the traditional drug delivery business model with one major exception – a patent-protected drug-delivery-enhancement product that offers properties superior to any competitive product. Another key success factor would be proprietary technology that can produce a portfolio of differentiated products that can be marketed by the company to specialists, general practitioners, or even the mass market. Companies that can deliver on these crucial factors are in the best position to take full advantage of the market forces currently shaping the pharmaceutical sector.
1. Valentine L; Business development: a barometer of future success.
J Commercial Biotech. 2003; 10:123-130