The patent cliff is beginning to reduce Big Pharma’s sales figures as generic versions of branded drugs enter the market. Although FDA has remarked that pharmaceutical innovation is beginning to increase, not all companies are going to be able to market enough new drugs to make up for lost sales. So how will these vulnerable companies maintain their profits?

Producing vaccines could be a key strategy for firms that have invested in biopharmaceutical manufacturing capacity. Market research firm Kalorama Information reported that the world market for preventative vaccines rose from $22.1 billion in 2009 to $25.3 billion in 2010. It predicts that the market will grow at a compound annual rate of 9.3% during the next five years, thanks partly to sales in emerging markets.

The vaccine market generally is regarded as having two components: adult products and pediatric products. The pediatric market is the bigger of the two—it accounts for more than half of the total market and is growing at a faster rate than the adult market, according to Kalorama.

The growth in pediatric vaccines could spur the development of new drug-delivery methods—another go-to strategy for drugmakers facing the patent cliff. Kalorama predicts that the market for needle-free drug delivery methods will grow at an average rate of 15.1% from 2011 through 2016, when it will be valued at roughly $6.2 billion. More and more children, and needlephobic adults, might benefit from products such as patches and pen injectors.

The search for alternatives to injections could produce surprising results. Arizona Biodesign Institute has concluded three early-stage clinical trials using potatoes that carry vaccines against hepatitis B, E. coli, and the Norwalk virus, according to Kalorama.

These two reports confirm the growing importance of vaccines and new drug-delivery methods for the pharmaceutical industry. Companies with enough manufacturing muscle and scientific knowhow should be able to find creative ways to survive the coming welter of patent expirations. And their ingenuity will make life easier for patients, too.

The capsules, which are made of polymeric hydrogels, are hollow except for polymer chains that are linked to the interior of the shell. These chains divide the capsule’s interior into various compartments that could contain several active ingredients. Possible applications include cancer therapy and pain relief.

The researchers formed the capsules in a two-step process. First, they formed chains of a temperature-sensitive polymer without using a cross-linking agent. The absence of this agent causes the chains to dissolve at a certain temperature. Next, the scientists added a cross-linking agent to a second polymer to create a shell around the temperature-sensitive polymer chains. Cooling the microcapsule caused the shell to swell until it reached its stable size, leaving behind temperature-sensitive polymer chains that can act as hydrophobic drug carriers.

The scientists are still trying to determine the best way to load drugs into the capsules and the best way to trigger them to release the drugs. Even though the capsules are still being refined, they have the potential to become a useful drug-delivery tool. Polymeric microspheres, while not new to the drug industry, can be a versatile delivery method. The straightforward process for creating the capsules also could attract drugmakers’ attention. The Georgia Tech team’s work provides cause for optimism at a time when some observers lament the lack of innovation in the drug industry.

The research, including the harmless operation of the magnetic pill system in rats using conventional gelatine capsules, was described earlier this week in the Proceedings of the National Academy of Sciences by researchers from Brown University in the US.

“With this technology you can now tell where the pill is placed, take some blood samples and know exactly if the pill being in this region really enhances the bioavailability of the medicine in the body,” Edith Mathiowitz, Professor of Medical Science in Brown’s Department of Molecular Pharmacology, Physiology and Biotechnology, said in a press statement.

In particular, the researchers envision that the technology could be used as a new drug delivery method for cancer drugs or drugs targeting GI diseases, as there are a number of therapeutics that would benefit from prolonged localization at their site of action or at the site of greatest absorption.

This is not the first time researchers have been attracted to the idea of controlling tablets magnetically, but, according to the press statement, it is the first time that magnetic forces have been controlled sufficiently to make the system safe for use in the body. The system developed by the Brown University researchers senses the position of tablets and holds them there with a minimum of force.

“The most important thing is to be able to monitor the forces that you exert on the pill in order to avoid damage to the surrounding tissue,” said Mathiowitz. “If you apply a little more than necessary force, your pill will be pulled to the external magnet, and this is a problem.”

The research is still in the early preclinical stages, but it’s promising that the researchers have been able to overcome the hurdle of making the system safe for use in the body. According to the statement, even after holding a pill in place for 12 hours in the rats, the system applied a pressure on the intestinal wall that was less than 1/60th of what would be damaging.

The next step will be to use the system to deliver drugs and test their absorption.

“Then it will move to larger animal models and ultimately into the clinic,” Bryan Laulicht, the lead author of the study, explained. “It is my hope that magnetic pill retention will be used to enable oral drug delivery solutions to previously unmet medical needs.”

Nanomedicine manufacturer Midatech Group (Oxford, England) and drug-delivery company MonoSol Rx (Warren, NJ) recently filed a provisional US patent application for “Nanoparticle Film Delivery Systems” that could transmit proteins and peptides through buccal or sublingual administration. The delivery system bypasses the gastrointestinal (GI) tract and sends medicine directly into the bloodstream. This mechanism could reduce side effects and prevent the GI tract from destroying the therapy.

About two weeks ago, the Georgia Institute of Technology gave Vyteris (Fair Lawn, NJ) the option to exclusively license its patented thermal-ablation and microdevice-fabrication technologies for transdermal drug delivery. The technology was developed to enhance skin permeation to the point where drugs with high molecular weight could be administered without injections or infusions.

These and other new technologies could one day challenge the dominance of injections as a method for administering vaccines. Considering how rapidly the market for vaccines is growing, drugmakers would do well to take notice of these exciting developments. Vaccinations might soon become as painless as freshening the breath with an oral strip. Maybe needles’ days are numbered.

Combination of a drug with a medical device could allow medicines to be delivered locally and thus maximize therapeutic effect and minimize side effects. But many manufacturers — particularly in Europe — are not fully aware of the benefits that combination products offer.

After chairing a session at the recent Pharmapack meeting in Paris (France) about the regulatory framework and procedures for combination products in Europe, Yves Tillet, Director at White–Tillet Consultants & Experts, spoke exclusively to Pharmaceutical Technology Europe to provide further insight. According to him, many companies do not yet realize the opportunities presented by combination therapies.

“The firms have their projects — and in the largest companies these projects are still tuned towards the search for blockbusters. Companies are under the influence of a culture they cannot dismiss overnight; however, the landscape is changing little by little,” he said. “For the moment, there is little noise about combination products, but as soon as the firms see the dangers and opportunities, they will jump on them.”

This changing landscape is partly due to the arrival of generic products and new competitors with biologic products, cell therapy and gene therapy products, which may require the development of new medical devices. “Thanks to new medical devices, there will be a revolution; that of drugs placed in situ with much lower amounts, thus protecting targeted tissues, as well as the liver and the kidney,” said Tillet. “Pharmacology will be changed.”

Combination products clearly offer a lot of promise for the future, but many manufacturers in Europe still lack a thorough understanding of the European regulations that govern these products. Some companies may even have been manufacturing combination products, such as asthma inhalers, for a while without realising it. In Europe, a combination product can be either a drug or a medical device, but the rule is less clear for certain borderline products and different EU member states may have different positions. However, there are plans to form a European Commission committee that will comprise representatives from member states. This committee will, in the absence of a consensus, take a supranational decision.

“The regulation on combination products was born with the regulation on medical devices and, in particular, with the 93/42/CEE directive applied in 1998. Previously, drug delivery devices were very few and inadequately assessed (only according to pharmaceutical standards). The devices were an accessory to the drug — hardly better than an excipient,” Tillet explained.

However, medical devices have now been developed, the functions of which are assisted by drugs. In some instances, for drug eluting stents for example, the European Medicines Agency (EMA), has published guidelines to assess drugs that assist the stents in their functions, however Tillet also added: “But in another way, except for some isolated cases, little progress has been made in the field of drug delivery devices. We are at the beginning of innovative in situ drug delivery concepts using sophisticated medical devices. The regulatory framework and project assistance provided by registration agencies should favor the emergence of new combination products.”

So should we expect a massive overhaul of the European regulatory system? “The current regulation should not evolve so much in the future — at least in its current framework,” said Tillet. “Rather, I see the creation of many guidelines to frame and standardize the development of these new combination products, with major actions taken to provide information and training on their good use.”

Dedicated solely to innovations in the pharmaceutical drug delivery and packaging industry, Pharmapack 2010, with its 224 exhibitors and 2550 visitors, was a breath of fresh air. Every exhibitor, from the small consultancy firms through to the multinational powerhouses, were housed in similarly sized booths within the bright and airy venue of the Paris Grande Halle de la Villette, and I think this made for a warm and welcoming atmosphere. Exhibitors were naturally restricted by the small exhibition space offered to them; they were less able to show off their latest technologies. But I do believe this made for a more relaxed atmosphere, primarily because voices were not drowned out by the whirring and pumping of machinery, but also because the smaller firms were able to stand as equals alongside their multi million- and billion-dollar revenue-generating counterparts. It is always great to see the fruits of our industry’s labor in action, but this meeting made for a refreshing change. 

So apart from enjoying the friendly atmosphere (and the fact that my feet did not feel as though they had been pierced by needles by the end of the day), I was wowed by some of the latest and greatest developments in the packaging and drug delivery industries. The packaging, labeling and security buzzwords that were flying around the event included: child-resistant, patient compliance, intelligent, sustainable, laser and diffractive coding, electronic monitoring, RFID, 3D product inspection, and more. Meanwhile, sustainable, disposable and environmentally-friendly solutions were the keywords used to highlight the areas where many of the drug delivery companies are currently concentrating their development efforts.

Rest assured that we will be reporting on some of the most exciting developments from the event over the coming months. One thing I can assure you is that our industry continues to innovate and the packaging and drug delivery solutions of tomorrow look fantastic!

Researchers at the University of California, Santa Barbara and at the University of Michigan used a polymer to create a doughnut-shaped template. The scientists coated the template with layers of hemoglobin and other proteins, then removed the core. The result was a particle that mimicked the size (roughly 5 µm in diameter), flexibility, and functionality of red blood cells.

The synthetic red blood cells can carry oxygen like their natural counterparts do. But unlike the real thing, these synthetic cells can encapsulate drug particles or carry them on their surface for controlled release. The scientists say that the synthetic red blood cells could carry several drugs at once. Also, the synthetic cells can be squeezed to flow through channels (e.g., capillaries) that are smaller than the cells’ diameter when they are at rest. Like real red blood cells, the synthetic particles can stretch in response to flow and regain their original dimensions after they exit a channel.

Although these synthetic red blood cells are still being studied, it’s conceivable that they’d have great advantages for drug delivery. Their composition and physical properties might bypass the body’s immune response and deliver drugs to areas that are otherwise hard to target. The cells’ adaptability suggests that they could be effective vehicles for multidrug therapies for diseases such as cancer or diabetes. The researchers’ invention seems like a creative innovation that could inspire the imagination of drug developers and formulators.

The two companies will work to bring needle-free vaccines, based on Intercell’s technology, to market. Intercell’s Vaccine Patch is a transcutaneous method of delivering adjuvant and antigen directly to the immune system. The adjuvant passes through the skin’s stratum corneum and activates cells of the immune system to take up the antigen and bring it to the lymph nodes. The Vaccine Patch contains the enterotoxin from Escherichia coli, an adjuvant and a powerful stimulator of the immune system. The companies believe that the technology could make vaccinations easier and more efficient.

The companies also hope to use Intercell’s technology to improve patients’ immune response to existing injected pandemic influenza vaccines. Intercell is developing a Vaccine Enhancement Patch that, in studies, has resulted in a seroconversion rate (i.e., the concentration of antibodies) of 70% after a single dose of vaccine. The companies say that the patch could expand vaccine supplies by allowing fewer or lower doses of vaccine.

If the technology proves sound, the GSK–Intercell agreement could change the way vaccines are delivered in the future. The Vaccine Patch could open the door to the development of vaccines that can’t safely be administered through injection, and it could certainly boost compliance among needlephobics. The deal may be a sign that a wider array of biologicals will soon be available for transcutaneous delivery.

The researchers created micrometer-sized capsules by wrapping metabolism-resistant material around spherical particles that they later dissolved in acid. The scientists filled the empty capsules by heating them in a solution that contained the drug compound. Heat made the capsules shrink, thereby trapping the drug inside. These capsules can be inserted into live cells through electroporation (i.e., the administration of a small electric shock).

In one experiment, the researchers exposed capsules to an infrared laser beam. The laser changed the structure of nanogold particles in the capsule and released drug into the host cell, which was unaffected by the laser beam. The capsules could also be made to release drug in response to a biological trigger such as a drop in blood sugar.

The researchers said that their technique could deliver DNA for gene therapy or insulin to manage diabetes. I imagine that it might also deliver small molecules. The capsules can be designed to be stable in the body to protect drugs that are easily degraded and store them for later use.

Like the magnetite nanoparticles, the micrometer-sized capsules are not ready for use in humans, but they seem full of possibility. To some patients, administration through electroporation might be more palatable than that through injection. This delivery method could enable various release profiles and might be appropriate for acute and chronic conditions.

Developments such as this are encouraging reminders of researchers’ ingenuity. One day, drugmakers and patients alike might benefit from this work.

The team encapsulated a drug in a specially engineered membrane that included magnetite nanoparticles. If you’re not up on your rocks, magnetite is a mineral that has magnetic properties. When a magnetic field is turned on outside the patient’s body, the magnetite nanoparticles heat up and collapse some of the gels in the membrane. This structural change opens pores that allows the drug to be delivered into the body within about one or two minutes. When the magnetic field is turned off, the nanoparticles cool, the gels reeexpand, and drug delivery is halted.

Aside from being totally cool, this drug-delivery method has several advantages. For starters, it doesn’t require any electronics to be implanted in the patient’s body. The membranes have not shown any toxicity or immunogenicity in studies. The gels would not collapse under normal body temperatures, or even fevers. And the method could potentially provide precise, repeated, long-term delivery of drugs on demand. It could be a good system for drugs that manage chronic pain, for example.

The magnetite-nanoparticle system is not yet ready for use in humans, but the research shows how ingenious and exciting some of the current research in drug-delivery methods already is. If funding for drug development stays at its current increased level, we might be seeing more fascinating delivery methods in the laboratory and, later, in hospitals and pharmacies.