Oral delivery is the most popular route of administration due to its versatility, ease, and, probably most importantly, high level of patient compliance. A recent PricewaterhouseCoopers report stated that compliance was one of the major issues for the healthcare industry and the leading cause of those recurring health problems that result in a significant rise in healthcare costs. The cost of noncompliance in the United States alone is an estimated $77 to $300 billion a year.1 Providing patients with simplified, convenient oral medications that improve compliance has been a major driver of innovation in the oral drug delivery market.
Within this market, controlled-release tablets and capsules will continue to create the largest demand, with adaptations such as chewable, orally disintegrating, nanoparticle, and combined technology formulations expected to broaden applications and revenues. The total market for oral medication adapted to delivery systems is forecast to reach $56.7 billion in 2012, up 7.1% percent annually from 2007 for the United States alone.2 Oral products represent about 70% of the value of pharmaceutical sales and 60% of the drug delivery systems market.3 The introduction of widely prescribed proprietary medicines in new controlled-release forms will be the driver of market gains.
Generally, controlled-release medicines can be categorized into two groups based on actions. Extended-release formulations deliver a portion of the total dose shortly after ingestion and the remainder over an extended time frame. One example of this formulation is Avinza, a once daily rapid onset extended-release morphine product. Delayed-release systems provide steady dosing after passage through the stomach. Typically, oral drug delivery systems are developed as matrix or reservoir systems.
Two of the most widely commercialized controlled-release technologies are the OROS delivery system developed by Johnson & Johnson’s Alza and Elan Drug Technologies’ Spheroidal Oral Drug Absorption System (SODAS) technology. Both of these technologies were initially developed for calcium channel blockers to improve the drug compliance of hypertensive patients. Other successfully commercialized technologies include Skye- Pharma’s Geomatrix, Eurand’s Diffucaps, and Flamel’s Micropump.
Evolution Continues
These and other technologies have evolved to address specific therapeutic needs such as pain and blood pressure. A number of companies are engaged in the development of pulsatile release systems, in which the drug is released in pulses separated by defined time intervals. Ritalin LA and Focalin XR, both used to treat attention deficit hyperactivity disorder, use pulsatile release to mimic the twice-daily dosing of a conventional immediate release tablet. These once-daily pulsed profiles offer the patient efficacy throughout the day, negating the need for a second dose during school hours. Ritalin LA and Focalin XR both utilize Elan’s SODAS technology.
Further manipulation of delivery systems has led to the development of chronotherapeutic systems, which take advantage of the natural biorhythms of the human body. Examples include Biovail’s Cardizem XL and UCB’s Verelan PM.
Orally disintegrating tablets (ODTs) are evolving into an important delivery system for drugs that treat medical conditions vulnerable to a sudden onset of symptoms. Such conditions include allergies, nausea, migraine headaches, and schizophrenia. Among the available ODT technologies are Catalent Pharma Solutions’ Zydis, CIMA Labs’ (Cephalon) Durasolv and Orasolv, and SPI Pharma’s Pharmafreeze systems. Catalent’s Zydis technology has been the most commercially successful, with numerous products launched through licensees.
Eli Lilly’s Zyprexa is among the widely prescribed drugs that have been adapted to the ODT delivery system. GlaxoSmithKline’s Lamictal ODT is the most recent product approved by the Food and Drug Administration (FDA). In May, GlaxoSmithKline announced that this product, which uses Eurand’s technology, is the first antiepileptic treatment available in an orally disintegrating formulation.
While there are a number of other delivery systems being developed, including chewables and transmucosals, advances in nanotechnology have recently provided one of the most significant opportunities for growth by addressing the estimated 40% of drugs with poor water solubility issues.4 Elan Drug Technologies’ NanoCrystal technology is one of the players in this area.5 Compared to conventional forms, oral formulations using NanoCrystal technology can enhance bioavailability, thereby reducing dose and size of dosage form; provide for rapid adsorption and onset; extend the range of dose proportionality, allowing for more drug to be delivered to the body; and reduce fed/ fasted variability, enhancing safety and efficacy (see Figure 1, p. 32).
Several of these benefits are embodied in marketed solid oral products, including Abbott’s TriCor 145 mg, Merck’s Emend, and Wyeth’s Rapamune. In-market sales for these three products were over $1.8 billion in 2008. Other technologies designed to overcome problems associated with poor water solubility include Skye-Pharma’s IDD solubilization technology, which has been used to launch Triglide for Sciele and Life Cycle Pharma’s MeltDose technology. Over the coming years, many more poorly water-soluble products should be launched with the aid of these and similar technologies.
Future Opportunities
While oral drug delivery is now considered an important drug optimization feature, many more advances are underway.3 For example, new drugs made up of a number of mini-tablets, each one formulated individually and designed to release drug at different sites, allow higher dose loading within the gastrointestinal tract and provide very flexible oral dosage options.
Incorporating mini-tablets of different sizes makes high drug loading possible. The TriLipix fenofibrate product launched by Abbott in January is composed of a number of mini-tablets. The PRODAS (programmable oral drug absorption system) delivery system from Elan Drug Technologies uses a similar approach.
Another area of opportunity is abuse-resistant delivery systems. At present, there are a number of initiatives working to minimize the risk associated with abuse of drugs, strong pain medications in particular. A record 36 million Americans have abused prescription drugs at least once in their lifetime, a U.S. government study found.6
Pain Therapeutics is considered the front-runner with its abuse-resistant formulation of oxycodone, which was made using Durect’s sustained-release gel-cap Oradur technology. In December 2008, Pain Therapeutics received a complete response letter from the FDA for its new drug application submitted for Remoxy in June 2008. To date, Remoxy has not been approved for marketing; the FDA believes additional non-clinical data will be required to support its approval.7
Other drug delivery companies at late-stage development include Alpharma with its morphine-based anti-abuse opioid Embeda, Elite with EL-216, and Acura with Acurox.8 It is estimated that the anti-abuse market, driven by oxycodone and morphine anti-abuse formulations, will create a $1.2 billion market by 2017.9
Another challenge—and opportunity—for the controlled-release market is alcohol-induced dose dumping. In 2005, Palladone capsules were withdrawn from the market in the United States and Canada due to dose dumping when co-ingested with alcohol. This problem is being addressed by a significant number of companies, including Flamel, which has developed Trigger Lock technology based on its Micropump platform. The Trigger Lock formulation of an opioid analgesic is being studied in two clinical trials.
Egalet’s key technology is an oral drug delivery system of capsules comprising a coat and a drug release matrix. The drug is distributed throughout the drug release matrix and is released over time as the coat and matrix are eroded within the gastrointestinal tract. Egalet says that because its technology is neither crushable nor injectable, it is difficult to extract, so it is not subject to alcohol-induced dumping. Other technologies designed to avoid or reduce alcohol dose dumping include Durect’s Saber technology, Soliqs’ Meltrex, and Banner’s Versatrol, a controlled-release softgel technology.
Combination Approaches
Advances in the oral controlled-release (OCR) market have seen companies looking to combine products and/or technologies to achieve better therapeutic effects. One newer initiative in this category, NitroMed’s BiDil product, involves combining hydralazine hydrochloride and isosorbide dinitrate. Drug combinations designed to help improve patient compliance have been a significant driver in the pharmaceutical industry for many years.
Combining approaches to overcome delivery problems of certain drug candidates will become more prevalent as companies push the limits of their technologies. Combining the NanoCrystal technology with their OCR platform, Elan Drug Technologies seeks to overcome problems associated with poorly water-soluble candidates while applying one of their OCR technology platforms to offer the additional benefits of modified or controlled-release properties and allow the drug to be processed into a solid oral dosage form.
Other approaches with significant potential include the targeting of drug directly to the colon and the stomach.10-11 Colonic drug delivery has attracted interest primarily for local delivery in diseases of the colon such as Crohn’s diseases, ulcerative colitis, and colorectal cancer. The colon has also been proposed as a better site than the small intestine to promote oral macromolecule uptake and is typically a site of drug absorption from extended-release preparations.
A variety of approaches are being investigated, including Alizyme’s Colal delivery system, which is in Phase 3, and Cosmo’s MMX technology, in Phase 2. Researchers continue to study gastro-retentive delivery—dosage forms are retained in the stomach to achieve a prolonged and predictable drug delivery profile in the gastrointestinal tract. One example of this type of delivery is Depomed’s AcuForm, a multi-hour, gastric retentive, controlled-release drug delivery system that allows for targeted, controlled delivery of pharmaceuticals to the upper gastrointestinal tract.
A review of the number of FDA approvals over the past years shows that new chemical entities (NCEs) have accounted for only 25% of all products approved; the majority of approvals have been reformulations or combinations of previously approved products (see Table 1, p. 34).12 With a new formulation costing approximately $40 million and taking four to five years to develop compared to the average cost of a next-generation product—in the region of $330 million—the potential for reformulation using oral controlled-release technologies has never been greater.13-14 Moreover, development of an NCE has been estimated to cost between $1.3 and 1.7 billion.15
In the face of financial pressures, it is no surprise that many pharmaceutical companies are turning to drug delivery companies to optimize their marketed products. An extra five years of patent life could generate 50% to 100% more revenue.16 Numerous drug delivery companies now offer a range of OCR technologies, many of which have been validated by product launches. Ongoing developments like the ones described here ensure that the OCR market will continue to grow in order to satisfy the demands of pharmaceutical companies and patients alike. n
Dr. Singh is senior director of oral controlled release, product development, and early stage development at Elan Drug Technologies. Reach him at gsingh.rekhi@elan.com or (770) 538-6321.
References
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