Improving Drug Delivery

Courtesy of Langer Research Lab, MITRobert Langer is a professor of chemical and biomedical engi neering at the Massachusetts Institute of Technology. He has written more than 800 articles, has more than 500 issued or pending patents worldwide, and has licensed his patents to 120 companies. In 2002 Langer was awarded the $500,000 Charles Draper prize, considered to be the Nobel Prize of engineering, and in 1999, Forbes Magazine named him one of the 25 most important people in biotechnology.Advan

Robert Langer
Sep 12, 2004
<p></p>

Courtesy of Langer Research Lab, MIT

Robert Langer is a professor of chemical and biomedical engi neering at the Massachusetts Institute of Technology. He has written more than 800 articles, has more than 500 issued or pending patents worldwide, and has licensed his patents to 120 companies. In 2002 Langer was awarded the $500,000 Charles Draper prize, considered to be the Nobel Prize of engineering, and in 1999, Forbes Magazine named him one of the 25 most important people in biotechnology.

Advanced drug delivery systems barely existed 25 years ago, but there has been such rapid research progress that more than 30 million people in the United States now use novel delivery systems each year. In general, advanced systems release a drug at a controlled rate for a prolonged period of time (as long as five years from a single implant), deliver the drug at specific sites in the human...

WHAT'S NEW

While drug-eluting stents are a good example of how to decrease toxic side effects by delivering a drug where it is needed most, several other delivery systems have come on the market in recent years. One such system is Risperdal Consta, which consists of injectable degradable polymeric microspheres that release an antischizophrenic drug for two weeks. It is the first controlled drug delivery system for mental health diseases, which historically have had low compliance rates. Another example is PEG-Intron, a long-acting delivery system for interferon consisting of polyethylene glycol polymers conjugated to interferon that can circulate for as long as a week in the bloodstream. The Alza Corp.'s Oros pill, a novel osmotic pump formulation, has been used to deliver drugs with fewer side effects, including Procardia XL, a calcium-channel blocker, and Concerta, which is used to treat attention deficit hyperactivity disorder.

Gliadel, the first local delivery system of an anticancer drug, is used to treat brain cancer. The product was the result of collaboration between myself, the neurosurgeon Henry Brem, and Guilford Pharmaceuticals, which licensed the technology. Ultimately the goal is to help people, and companies can provide the money and the infrastructure to make sure patients get the benefits of new scientific research. Gliadel currently has sales of roughly $30 million per year (lower than some delivery systems), because few people have brain cancer. However, it is important because it can extend life and relieve suffering for patients. It's also a paradigm shift, because it establishes that you can deliver chemotherapy locally and do it safely and effectively.

These are some exciting advances in the field and there are surely more to come. In the 1970s I was one of only a handful of people who believed in better drug delivery; now it's great to see a whole industry working on improving the lives of millions of people. Scientists are exploring nearly every part of the body as a means of either delivering the drug to that body part or as a portal to the systemic circulation.3These include the skin, the nose, the lungs, and the intestine.

FUTURE DRUG DELIVERY

One area that has received a great deal of attention is the oral delivery of macromolecules, such as proteins. A variety of barriers must be overcome to achieve this, but if successful, it would not only permit the delivery of proteins such as insulin or interferon, but also perhaps genes.

One barrier to the oral delivery of macromolecules is stomach acid, which readily destroys most proteins. This can generally be overcome by using enteric coatings, but one might also add protease inhibitors to the formulation to prevent protease-related destruction. However, the biggest problem is getting certain drugs to pass through the intestinal wall into the systemic circulation. One strategy entraps proteins in bioadhesive micro-spheres that can attach to the intestine and slowly release a drug. Edith Mathiowitz and colleagues at Brown University have used such molecules to deliver insulin in animal models. She has launched a Providence, RI-based company, Spherics, to commercialize bioadhesives.

The skin is a relatively impermeable barrier to most drugs, although transdermal patches for nicotine and estradiol have led to new therapeutic approaches. To make transdermal delivery of molecules practical, electrical approaches are being studied. For example, iontophoresis, which involves passing a small electric current through the skin, has provided enhanced transport for low-molecular weight molecules and is being used to deliver pain medications more rapidly. Ultrasound, which has also been used to enhance skin permeability by temporarily disordering the lipid bilayers in the skin's outermost layer, is in clinical trials for delivering insulin and pain medications and for detecting glucose transdermally.34

Lung delivery represents another challenge. Generally, less than 10% of a drug delivered by a conventional inhaler reaches the lung. In addition, repeated delivery every few hours is often necessary because lung macrophages clear most drugs rapidly. A variety of researchers and companies have developed novel inhaler designs, and recently, new aerosols have also been created. One approach has been to design large, highly porous aerosol particles with extremely low densities. By lowering aerosol particle density and increasing aerosol particle size, the aerodynamics of the aerosols are altered and much larger particles can enter the lung using a small and simple inhaler. This also decreases aerosol aggregation and macrophage phagocytosis, resulting in sustained drug release.5 The approach is now being used to deliver many drugs such as insulin, human growth hormone, and epinephrine.

Other research areas involve nanotechnology and microelectrical mechanical systems (MEMS). Drugs can be delivered via microchips containing wells loaded with a drug. The wells, which have nanoliter volumes, have gold covers that can be dissolved by applying an external, one-volt signal. This can be done selectively to any of the covers, releasing the drug inside the well.6 Hundreds of wells can be placed in a single small chip, and recently, the chips have been made of completely degradable components.7One might eventually envision chips containing biosensors that can detect chemical signals in the body and release drugs in response to such signaling.

HIGH THROUGHPUT FOR DRUG FORMULATIONS

<p>THE FUTURE OF DRUG DELIVERY?</p>

Courtesy of Dana Lipp

These implantable drug-laden microchips are part of a microelectrical mechanical system (MEMS) that delivers medicine after a 1-volt signal dissolves the gold foil that covers the drug well.

The pharmaceutical industry has been placing increased emphasis on pharmaceutical formulations. In 2002, more than half of all new drug applications approved by the FDA were new drug formulations. The creation of such formulations may benefit from applying the concepts of high-throughput automated technologies. For example, automated high-throughput crystallization platforms have been developed that are capable of screening as many as 18,000 drug crystallization conditions in parallel. This approach has already led to the creation of three new crystal forms for ritonavir, a drug that was removed from clinical distribution because it converted into a thermodynamically more stable form than the one originally approved by the FDA.8

Targeting drugs to specific cells in the body is a future goal of drug delivery research. Perhaps antibodies or appropriate sugars might be complexed with drug delivery systems to achieve this objective. Another goal is to develop new ways to deliver allergens and vaccines that would avoid the current scheme of multiple injections, which is particularly problematic in the developing world. A third important area of research is delivery of drugs to poorly accessible sites such as nerves, sinuses, and the back of the eye. Delivery of DNA and, most recently, siRNA represents another important challenge, as does the delivery of mammalian cells for cell-based therapy. Researchers will continue to focus on these and other challenges as advances in drug delivery systems are expected to continue at a rapid pace, making newer and better therapies available for patients.

Robert Langer rlanger@mit.edu