Devices that enable the timed release of drugs into the body, whether they are transdermal patches or implants, are already familiar, but their range of applications is growing rapidly as the technology advances.
Their potential to treat a broader range of conditions and significantly improve therapeutic results is leading pharmaceutical companies to work closely with device manufacturers to accelerate the development of combination products. Global medical products contract manufacturer ISSAC Medical is well placed to further the capability of combination products through two subdivisions that together make it a complete US Food and Drug Adminsitration (FDA) registered, ISO certified “design through distribution” solution for medical products OEMs.
Specialty Silicone Fabricators is the world’s preeminent manufacturer of ultra-high precision specialised silicone medical products, and Innovative Surgical Products is a world-class provider of medical products assembly and packaging. Marketing director Paul Mazelin gave us the inside track on how combination products will define drug delivery.
Medical Device Developments: What are combination products and what are their advantages over other methods of drug delivery?
Paul Mazelin: The US FDA actually defines four types of combination products. Two are of particular interest to ISSAC Medical. First, “a product comprised of two or more regulated components, ie, drug/device, biologic/device, drug/biologic, or drug/device/biologic, that are physically, chemically, or otherwise combined or mixed and produced as a single entity”. Second, “two or more separate products packaged together in a single package or as a unit and comprised of drug and device products, device and biological products, or biological and drug products”.
Combination products offer several advantages compared with drug delivery via oral, injection and infusion methods. All drug-device type combination products exhibit one or more of the following attributes.
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First, they provide controlled release of the active pharmaceutical ingredient (API) instead of bolus-type delivery. This allows API concentrations to be consistently maintained within an optimal therapeutic range. Second, drug-eluting devices, particularly implanted devices, allow for a targeted delivery of the API. This targeted approach, when contrasted with systemic administration, permits higher therapeutic dosages to be delivered while minimising adverse side effects. Third, combination products have been shown to improve patient compliance. Most healthcare practitioners now agree that within an ageing population, compliance becomes less certain and, therefore, more important.
MDD: How have we arrived at the point where combination products are so important for the future of drug delivery?
PM: Let’s consider the two sectors most directly involved in combination product development – the pharmaceutical and medical device industries. The pharmaceutical industry in particular is under pressure. Retail prescription drugs now account for about 10% or $220bn of annual US healthcare expenditures. A recent study showed that retail prescription prices have increased on average 8.3% annually between 1994 and 2004. Consumer and government groups are lobbying the industry to moderate price increases. At the same time, the cost to launch a new drug has skyrocketed from $138m in 1975 to over $800m today.
While it may involve drug discovery, combination product research is primarily focused on developing novel ways of introducing drugs to the body. The costs of this development are lower than drug discovery but the benefits to the industry and consumer can be significant. In many cases existing drugs have been shown to exhibit greater efficacy at lower cost when delivered as a combination product.
It gets even more interesting though. Historically, only five out of 10,000 compounds investigated reach clinical studies. Of these, only one will be approved for human use. The pharmaceutical industry is now relooking at these “dry holes” and early results suggest that many abandoned drugs may be safe and effective when delivered as a combination product. This is a huge and developing story.
The medical device industry looks at combination products differently. For this group the impetus is to build a better mousetrap. Paclitaxel-eluting coronary stents and steroid-eluting pacemaker leads are examples. In both cases an existing medical device was improved by incorporating an API.
Drug-eluting devices have been shown to result in improved patient outcomes when compared with non-eluting devices. Furthermore, medical device companies that have been early movers in this area are seen as innovators, which differentiates them from their competitors.
MDD: In what applications are combination products used?
PM: It’s a huge and rapidly growing list. For example, the National Institutes of Health lists 20 APIs that are found in approved transdermal patches. Indications include hypertension, chronic pain, menopausal symptoms, smoking cessation, ADD, testosterone deficiency, motion sickness, dementia and Parkinson’s disease to name a few, and many more APIs are being investigated.
The list of implanted combination products is equally large and diverse. Implanted drug-eluting devices often represent best practices in areas including interventional cardiology, ophthalmology, urology and women’s health.
MDD: What scope is there to increase the range of applications?
PM: In a word, unlimited. I’ll give you two examples. First, we are in discussions with a client regarding a drug-eluting ophthalmic implant. The API will be processed using a hot melt extrusion (HME) process; really cutting-edge technology. The HME process allows the API to be dispersed during extrusion as discrete molecules, forming a solid solution. Solid solutions increase the solubility of the API, making it more effective. The buzz phrase is “enhanced bioavailability”.
Earlier I mentioned that big pharma was reinvestigating expensive drugs that had been abandoned. Recent indications are that some of these compounds, when processed using HME technology, may now be safe, effective and even more potent than expected. The cost savings and profit potential for the pharmaceutical companies are tremendous and we’re delighted to be participating in this sort of radical innovation.
A second example involves advances in transdermal drug delivery. Transdermal patches have generally been grouped into two categories, either matrix or reservoir type devices.
While delivery kinetics differ between the two, both types involve the same passive transport of APIs across a concentration gradient. A process called iontophersis is shaking things up.
This process creates positive and negative charges within a small skin patch. The effect is that high concentrations of charged API and other bioactive agents can be propelled transdermally using repulsive electromotive forces. We’ve been involved in microelectronic assembly of implants for several years and we hope to participate in this innovation in the transdermal market.
MDD: How fast is the market for combination products likely to grow?
PM: A few years ago, a seminar held in San Jose was geared towards the venture capital community and a group of combination product technologists. It was billed simply as “Combination Products – The Future of Medicine”. Only time will tell whether combination products are indeed the future of medicine or merely another important tool that advances medical care. Revenue and projected trends may be a more reliable indicator. Earlier this year a consultancy noted that the US drug-device market is expected to account for $10.6bn in revenue and that the sector has been growing at a rate of about 15% for the past two years.
Another group notes that global revenue from transdermal drug delivery products exceeded $10bn in 2007 and is expected to double by 2014. In a nutshell, we’re reasonably certain that the rate of growth in the combination product market is outpacing the pharmaceutical and medical device sectors. As importantly, we see this growth rate differential increasing in the future.