Beginning this month, we are featuring monthly reader polls to gain your feedback on key advances in the pharmaceutical sciences and manufacturing. As the scientists and technical experts on the front lines, your input is a crucial component in understanding what the industry has achieved and where it will go in the future. We encourage you to provide your feedback in our first poll, which is examining advances in oral drug delivery and oral product forms. We will share the results with you at PharmTech.com, and along with further analysis, our July issue will take a retrospective and prospective look at drug substance and finished drug-product manufacturing, formulation development and drug delivery, outsourcing, and analytical testing.

We are interested in your feedback as well. In addition to our reader polls, we invite you to provide your input on what you think have been major achievements in drug substance and finished drug-product manufacturing, formulation development and drug delivery, outsourcing, and analytical testing. Lend your expertise and offer your input in the comment section to this blog or email your input to Patricia Van Arnum, executive editor, pvanarnum@advanstar.com. We look forward to hearing from you.

Topical formulations can be used to treat local and systematic indications, offer ease of delivery, facilitate patient compliance, and avoid the problem of first-pass metabolism. Successfully developing a topical formulation requires an understanding of the physiochemical properties, such as release characteristics, composition of the drug-delivery system, and the nature of the drug-delivery vehicle. Manufacturing a semisolid dosage requires implementing a CMC (chemistry, manufacturing, and controls) strategy to ensure stability, photosafety, avoidance of product degradation, and minimization of process impurities. The Pharmaceutical Technology webcast, “Optimizing Topical Drug Formulation and Manufacturing,” provides insight on recent advances in topical drug formulations, the latest regulatory/pharmacopoeial requirements in product quality and product performance, and strategies to optimize manufacturing for topical drug products.

Speakers include: Vinod Shah, PhD, chair of the Special Interest Group, Regulatory Science of the International Pharmaceutical Federation and distinguished pharmaceutical scientist and consultant to the US Pharmacopeia; Majella Lane, PhD, senior lecturer in pharmaceutics at the School of Pharmacy at the University of London; and Michael Lowenborg, R&D manager of formulation and process development at  DPT Laboratories.

Additional information and registration for the webcast may be found here.

Topical formulations can be used to treat local and systematic indications, offer ease of delivery, facilitate patient compliance, and avoid the problem of first-pass metabolism. Successfully developing a topical formulation requires an understanding of the physiochemical properties, such as release characteristics, composition of the drug-delivery system, and the nature of the drug-delivery vehicle. Manufacturing a semisolid dosage requires implementing a CMC (chemistry, manufacturing, and controls) strategy to ensure stability, photosafety, avoidance of product degradation, and minimization of process impurities. The Pharmaceutical Technology webcast, “Optimizing Topical Drug Formulation and Manufacturing,” provides insight on recent advances in topical drug formulations, the latest regulatory/pharmacopoeial requirements in product quality and product performance, and strategies to optimize manufacturing for topical drug products.

Speakers include: Vinod Shah, PhD, chair of the Special Interest Group, Regulatory Science of the International Pharmaceutical Federation and distinguished pharmaceutical scientist and consultant to the US Pharmacopeia; Majella Lane, PhD, senior lecturer in pharmaceutics at the School of Pharmacy at the University of London; and Michael Lowenborg, R&D manager of formulation and process development at  DPT Laboratories.

Additional information and registration for the webcast may be found here.

The communication was directed at the use of jet-injector devices to deliver seasonal influenza vaccines.  Jet injectors are devices that deliver a high-pressure fluid jet through the skin to deliver medications and vaccines subcutaneously or intramuscularly. Some large retailers had been promoting “needleless flu shots” using jet injectors, but stopped after FDA issued its warning.  According to FDA, the inactivated influenza vaccines are only approved for delivery by sterile needle and syringe, and the requisite evidence has not been obtained to approve other delivery methods.

According to the communication,  “When the FDA approves a vaccine, the approval is based on scientific information demonstrating the safety and effectiveness of that vaccine in a given population (e.g., children, adults or the elderly), using a specific dose, schedule and method/route of administration.  Changes in the dose, route and/or method of administration have the potential to impact the effectiveness and the safety profile of a vaccine.” Furthemore, “Jet injectors that have been cleared by FDA to deliver medications and vaccines should be used to deliver only those medications and vaccines that have been approved and specifically labeled for use with a jet injector.”

Besides having to endure vaccination with a needle, the other bad news is that seasonal flu shots may not be as effective as one would like.  According to an article published online Oct. 26, 2011, in The Lancet Infectious Diseases, flu vaccines are only moderately protective, work better in young children than in adults, and protection can vary with season.  The study was a meta-analysis of studies published between 1967 and Feb. 2011 that examined vaccine efficacy in a randomized, controlled setting.

As for me, I’d rather be 59% protected than not at all, so I’ll brave the needle.  Besides, it’s for the good of public health.

A few weeks ago, Representative Michele Bachmann (R-MN) made waves by claiming that the vaccine for human papillomavirus could have dangerous side effects. She retreated from her remarks after the American Academy of Pediatrics said that they had no scientific validity. Makers of biopharmaceuticals might feel vindicated, but a recent poll emphasizes that Bachmann is not alone in her views.

About 21% of respondents to an NPR–Thomson Reuters Health Poll believed that autism was linked to vaccines, and 7% believed that diabetes was linked to vaccines. Nearly half of the respondents worried about the side effects of vaccines, and about the same portion were concerned about their long-term effects on health. About a quarter of respondents said that their opinions about vaccines had changed during the past five years.

Patients’ concerns about vaccines’ safety are not supported by the evidence. Federal officials have studied vaccines’ links to side effects 12 times in the past 25 years, and the most recent report from the Institute of Medicine (IOM) found inadequate evidence to accept a causal relationship in the vast majority of cases. IOM did, however, find evidence to reject relationships between the measles–mumps–rubella (MMR) vaccine and autism, and between that vaccine and diabetes.

IOM did find links between vaccines and some adverse events, but the events were either rare or transient. For example, patients vaccinated against chicken pox can develop pneumonia, hepatitis, or meningitis late in life if an unrelated illness (e.g., cancer) compromises their immune system. In addition, the MMR vaccine was linked to temporary joint pain in children and female adults.

Biopharmaceutical manufacturers that are confident of their products’ safety could still benefit by launching a public-education program. Publicizing the many federal studies that have found vaccines to be safe and, as I wrote a few weeks ago, disclosing safety information gained during trials of approved vaccines could help to assuage patients’ fears.

This week, it wasn’t a vegetable that commanded the media’s attention (although this morning I did come across a piece touting the benefits of spicy broccoli for fighting cancer); instead, the flower, the British Autumn crocus, stole the spotlight following the release of a press statement from the UK’s University of Bradford. According to the statement, researchers have created a drug that has the potential to find and destroy solid tumours, regardless of cancer type.

The drug’s key active agent is based on colchicine, a natural compound that was derived from the crocus. Most media headlines have sensationalised the research (examples include: Tumors effectively cured with crocus drug,  Crocus drug that can kill tumours in one treatment with minimal side effects and Flower-powered ‘smart bomb’ to beat cancer, scientists say), but when you look beyond the hype, there’s some intriguing science.

Colchicine is well-known for its anti-cancer properties, but is highly toxic against normal tissues in the body. The researchers, however, have designed a delivery system that prevents colchicine from being active around the rest of the body where it could damage normal cells. The release of colchicine is triggered by an enzyme from a family of proteases called Matrix Metalloproteinases (MMPs), which is only usually present in high amounts in tumours.

“One role of this particular MMP in cancers is to dig a path for the tumour to grow bigger and develop new blood vessels that will help nourish the tumour,” Professor Laurence Patterson, Director of Bradford’s Institute for Cancer Therapeutics (ICT), explained in a statement. “Our novel delivery method uses the presence of this active MMP to activate the drug which attacks and breaks down cancer blood vessels, destroying the tumour’s lifeline.”

Five different types of cancer have been tested in the laboratory using mice — breast, colon, lung, sarcoma and prostate. According to the researchers, in one study, half the mice showed complete tumour remission after a single dose. The team is now in discussion with a funder to take the drug through the final stages of preclinical assessment, after which clinical trials are planned to start at St James’s University Hospital in Leeds.

Back to reality

The research (and the accompanying media sensationalism) has caused a massive stir, but the UK’s Cancer Research was charity was quick to point out in a detailed blog that the research is a long way from curing human cancers. There’s also no guarantee that it will ever be possible to translate the findings into humans (see my related blog post A Rat is Not a Human!).

Cancer Research also points out something else; the press release seems to be based on peer-reviewed work that the researchers published in July 2010. “As far as we’re aware, the team haven’t published any new results since their 2010 paper,” said Cancer Research.

It’s not all disappointing news, however. The research is still a step forward in the fight against cancer and Cancer Research admits that the research is intriguing, although it does remain cautious in its outlook.

“The researchers’ results so far are impressive, but they’re just one of several hundreds of similar intricate approaches taken to tackle cancer by researchers around the globe, which are generally referred to as ‘enzyme-prodrug therapy’, and involve activating a harmless form of a drug near or in a tumour… Overall it’s fair to say that this kind of approach is still at a relatively early stage, although the Bradford results are certainly impressive, and their beauty is in their relative simplicity.”

Related blogs and news from PharmTech
Sensationalizm Strikes Again

Research Spend On Cancer Doubles Within A Decade

A Rat is Not a Human

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.

Last week, Sanofi Pasteur, the vaccines division of Sanofi, reported that FDA approved the company’s supplemental biologics license application for Fluzone Intradermal, an influenza vaccine that is delivered through a microinjection system. Sanofi said the new formulation, Fluzone Intradermal, is the first influenza vaccine licensed in the US that uses a microinjection system using intradermal delivery. The vaccine is delivered with an ultra-fine needle that is 90% shorter than the typical needle used in intramuscular injection of an influenza vaccine, according to a Sanofi press release. Sanofi Pasteur also licenses microinjection intraderaml influenza vaccines, marketed as Intanza or Idflu, in 40 countries, including Australia, Canada, and countries in Europe, where it received approval in 2009.

The Fluzone Intradermal vaccine uses a prefilled microinjection system that is designed to deposit vaccine antigens into the dermal layer of the skin. The dermal layer of the skin contain a high concentration of dendritic cells, which play a role in generating an immune response. The ultra-needles used in the delivery are 0.06 inches in length, compared with typical needle lengths of 1 inch to 1.5 inches for needles used in intramuscular delivery.

Less invasive delivery methods, such as microneedle drug delivery, may present alternatives to make biopharmaceuticals an attractive option. Even though a biologic drug may offer an improved mechanism of action and clinical efficacy, that therapeutic advantage has to be balanced with how the drug is administered and delivered to gain patient acceptance and compliance. Such considerations may not factor strongly into therapies for more difficult-to-treat diseases (i.e., cancer and neurological disease), where the delivery method is secondary to finding a drug of clinical benefit. More patient-friendly approaches in drug delivery, however, are important for biopharmaceuticals to effectively compete against orally administered small-molecule drugs when these drugs may be considered to be adequate in more common therapeutic areas or in differentiating among other parenterally delivered biologic-based drugs. As the pharmaceutical industry builds its biologic-based drug pipeline and with it, a product life-cycle management strategy, “delivering the goods,” takes on a new level of importance.

For additional information on transdermal drug delivery, see the PharmTech article, “Transdermal Delivery of Vaccines and Proteins.”

One of the paper’s authors, Dr. Richard Weisler of UNC states in the release that “To put this in perspective, the number of 2007 U.S. unintentional drug poisoning deaths alone represents tragically about 4.6 times as many deaths as all U.S. fatalities in both Operation Iraqi Freedom and Operation Enduring Freedom in Afghanistan from the beginning of both wars through Feb 20, 2011.”

FDA’s response to the problem has been a series of educational initiatives for patients and physicians. Drug makers have responded by developing innovative formulations to discourage abuse of prescription opiates. This type of formulation work runs counter to the type of strategies that usually concern drug makers: generally, the idea is to get the drug to its target at high concentrations as fast as possible for as long as possible. In the case of opiates, they are tasked with getting the drug to target at therapeutic concentrations, but making it impossible to reach concentrations that are too high or reach them too quickly.
This week, Pain Therapeutics Inc. released results from its Phase III trials of its opiate REMOXY, an encapsulated, water insoluble, highly viscous, twice-daily oral formulation of oxycodone. The study met its endpoints, finding that patients did not like REMOXY as much as oxycodone, and could not chew it for more than 1.5 minutes, due to its unpleasant taste and texture. For this class of drugs, developing one that’s liked less than the competitor, and tastes terrible represents a rousing success.