The stellar growth of the pharmaceutical industry in the 1980s and 1990s has slowed during the last few years. In 1998, FDA approved 41 new molecular entities, but in 2002, according to a report by market research firm IMS Health, Westport, CT, the agency approved only 17, the fewest since 1983. The report also stated that sales increased 11.8 per cent in 2002 to $192 billion, compared to nearly 17 per cent in 2001.
These kinds of numbers have worried pharmaceutical companies that are now scrambling to maintain or enhance their product offerings by turning to advances in tablet technology such as sophisticated excipients, extended-release formulations, fast-dissolve tablets and self-repairing tablets.
According to analysts, the pharmaceutical industry will start focusing on formulation and manufacturing to enhance the bottom line. There is now an internal drive towards profitability that wasn't that strong five years ago. Three trends are noticed in the evolution of the industry and tablet technology: Using low-dose drugs for small molecules, using controlled release to extend patent lives and getting macromolecules into a tablet form. A lot of effort is going into this area.
Novel Drug Delivery
Coming up with novel ways to deliver drugs is key to maintaining profitability, the whole industry is facing lack of drugs in the pipeline and they're all struggling to come up with other ways of making money; this means reformulating in some way.
One approach, is to use technologies such as mouth-dissolving tablets, also known as fast melt, fast dissolving or orodisperse. Schering-Plough's Claritin RediTabs use a mouth-dissolving technology, Zydis, developed by RP Scherer Corp., now a subsidiary of Cardinal Health. The Zydis dosage form, which dissolves on the tongue instantly, is for patients who find swallowing conventional solid-dosage forms difficult, unpleasant or inconvenient. Zydis is used in Zyprexa, a drug developed by Eli Lilly and Company for schizophrenia or acute bipolar mania. Other companies have developed mouth-dissolving tablets, including Janssen Pharmaceutica (Quicksolv), Yamanouchi Pharma Technologies (WOWTAB) and Elan Corporation (Fast Melt). Fast melts have taken off since the success of Claritin, creating a lot of interest in this type of formulation, says Hughes.
Extended-Release Dosage
An area continuing to evolve is extended-release dosage forms. Though extended release has been around for a while, it is becoming more and more sophisticated and companies are using newer materials that are covered by patents. It extends the life of the drug so that people shift from three-times-a-day dosing to the new extended-release tablets, taking them just once or twice a day. Generics can't move into that area unless they feel that they can break the patent, which is not easy.
An approach called "pulse technology" could help patients taking cyclooxygenase-2 inhibitors such as Celebrex and Vioxx for osteoarthritis pain. "Older people who tend to take these drugs wake up in the morning with pain and then take the tablet. New delivery tools allow patients to take the tablet at bedtime and the active drug won't be released until maybe six or eight hours later. There's a type of pulsed release where none of the drug is released and then several hours later it is all released," explains an expert.
Self-Repairing Tablets
BASF has developed a new raw material that helps protect tablets from mechanical stress. The sustained-release film coating is called Kollicoat SR 30 D. (SR stands for "sustained release" and 30 D means it is a polyvinyl acetate at 30% dispersal). "If you put the tablet under stress-punch, break or heat it-it's supposed to hamper the release profile. But this polymer has a self-repairing ystem so that even if you puncture it with a needle, the dissolution will not change," he says.
Tablets coated with Kollicoat SR 30 D were subjected to strong mechanical stresses, including a friability test (500 revolutions, 15.5cm drop height) and 20 drops from a height of 1.5m. Neither had any noticeable effect on the release characteristics. Tests on isolated films show that Kollicoat SR 30 D has far greater elasti-city than ethyl cellulose or ammonio methacrylate copolymer. In addition, the release rate can be adjusted by using water-soluble polymers and by varying the coating thickness.
BASF is also working on an immediate-release film coating. The company has developed a polymer that can reduce the processing time of the film coating because its viscosity is low.
More Sophisticated Excipients
High-functionality excipients are another emerging trend in tablet technology. PROSOLV, developed by JRS Pharma, became commercially available a few years ago. Since then, three drugs in the US and three in Europe that use the technology have been approved by regulatory agencies.
PROSOLV is considered the most significant invention in this area of pharmaceuticals in 30 years. "There is a tremendous interest in using PROSOLV for companies to do what they had always dreamed about doing-direct-com-pression formulations with low-dose drugs that have equivalent or superior content uniformity to wet granulation. About 20 or 30 years ago, the dream was direct compression with traditional excipients, which worked pretty well, but when it came to low-dose drugs, content uniformity became the issue. With PROSOLV, you can now take it one step further and convert these drug targets to direct compression."
PROSOLV allows for greater drug dispersion and content uniformity; and yields extremely good flow and compaction.
Effervescents Emerging?
Unlike high-functionality excipients, effervescents are not new, having been used in OTC products like Alka Seltzer for years. A majority of effervescents today are used in neutraceuticals but that could change in the coming years, says Rifat Parvez, PhD, of PIL, a manufacturer of effervescent excipients in Dayton, NJ. Effervescents' major advantage is that the drug product is already in solution at the time that it is consumed. This way absorption is a lot faster and more complete than with a tablet or a capsule.
Effervescents offer an alternative to standard tablets that some patients may find difficult to swallow and can have a buffering effect against pH changes in the gastrointestinal tract, improve tolerance after ingestion and improve palatability. But effervescents have been ignored because they do not always dissolve into a clear solution, a factor that has made them less popular with consumers.
The formulation of sodium bicarbonate and citric acid makes conventional effervescents "very, very" unstable. From the very beginning of the manufacturing process, it requires very low humidity and temperature surroundings. The effervescent that we have doesn't require those stringent low humidity and temperature requirements, so that's a big expense that can be eliminated, opine researchers.
PIL produces two effervescents, Efferves SGC, a combination of glycine carbonate and glycine citrate, and Efferves LC, a combination of L-lysine carbonate and glycine citrate that can be used in sodium-restricted formulations. Glycine plays an important role in dissolution and absorption; because it is neutral and amphoteric, it is an efficient buffer in both acidic and basic pH ranges.
Process Analytical Technology
Improving excipients and other ingredients can make drug delivery much more effective at lower costs, but those benefits can be mitigated when quality control problems arise during manufacturing. That's where process analytical technology (PAT) plays a role. With PAT, state-of-the art technology using laser and infrared sensors provide real-time information on active ingredients, inactive ingredients and the distribution of moisture in a product.
PAT monitors literally every tablet that passes under the device so that manufacturers can have a general measure of quality.
Much work needs to be done to integrate laser and infrared technology into the drug manufacturing process. FDA has launched a PAT initiative and formed a subcommittee with representatives from pharmaceutical and generic manufacturers, consultants to the industry and government officials. " efficiency, according to an FDA statement.
PAT is a very recent development and it is being encouraged by FDA because they see the value of it, especially at the beginning and at the end of the batch where, because of the transfer from the previous batches, you usually have less.