Using a new three-dimensional printing device similar to a computer inkjet printer, MIT scientists have been able to "print" drugs into pills, creating highly precise doses that they say will be more effective and have fewer adverse side effects.
The scientists say this is the first solid free-form fabrication device that can form tablets using pharmaceutical-grade materials. "The technology represents a new way of formulating drugs with unprecedented dosage control," said Professor Michael J. Cima of the Department of Materials Science and Engineering (MSE).
Professor Cima and Professor Emanuel M. Sachs of the Department of Mechanical Engineering co-developed 3-D printing eight years ago to produce solid parts with intricate architectures. The technology originally was used to make ceramic molds for investment-cast car and airplane components.
Professor Cima applied 3-D printing to drug-making with MSE graduate students Benjamin M. Wu, DDS (who is also a postdoctoral fellow at the Harvard School of Dental Medicine), and Robert D. Palazzolo. A fourth member of the team is C. William Rowe, a visiting scientist in the Materials Processing Center and a senior scientist at Therics Inc., the Princeton, NJ, pharmaceuticals maker that has the exclusive license to commercialize the 3-D drug-printing technology. Therics sponsored the research.
The scientists presented their work on April 13 at the American Chemical Society national meeting in San Francisco. The researchers introduced the 3-D printing technology to the ACS two years ago, Dr. Wu said, but at that time they had only continuous-jet technology making non-pharmaceutical-grade tablets. This time they will demonstrate the integration of both continuous-jet and drop-on-demand technologies on one 3-D printing machine, and the fabrication of tablets from FDA-approved pharmaceutical-grade materials.
Three-dimensional printing works by dropping precise drug doses onto thin layers of fine powder as the tablet is formed. Pharmaceutical-grade powder which forms the structural matrix of the pill is then spread to form the next layer, which is 100-150 micrometers thick. The continuous-jet printhead then sprays pharmaceutical-grade binder. Some 30-50 layers are required to complete the building process, but hundreds or thousands of pills can be produced at once. The drop-on-demand technology can place dots of one drug or multiple drugs very precisely throughout the layers for the most effective release.
In contrast to continuous-jet printing, which delivers a fluid under pressure, drop-on-demand technology only forms droplets when an electrical pulse signal is applied. Drug waste and contamination of the powder bed with other drugs that may be deposited into the same tablet are therefore reduced.
Traditionally, pills are made by mixing pharmaceutical powders, binders and drugs, compressing them into tablet form, and coating them. "With our technology, we can deposit drugs very precisely," said Dr. Wu. "We will be able to provide pharmaceutical scientists with the technology and design rules to rapidly manufacture tablets with customized drug-release profiles in order to optimize pharmacokinetics and therapeutic requirements."
The effectiveness of a drug for a given illness depends on many factors, including the patient's age, gender, diet and weight. It also depends on when the drug is taken. For example, medicine for high blood pressure is best taken before waking up, because the most likely time for an angina attack is about one hour after getting out of bed.
Conventional pills release medicine continuously, so medication taken before going to sleep will not last until the next morning. But with 3-D drug printing, the placement of drops on the layers and the use of different binders all allow for precision time-control of drug release. Thus, a patient could take a tablet before going to bed, but the drug would be released one hour before he or she awakens.
"Some drugs don't work well if they are released continuously. Our technology works more like an injection," said Dr. Rowe. "The goal of controlled time releases is to better match the pharmacology of drug absorption."
Implantable drugs also release drugs continuously, and the drug release rate decreases over time. Current implants, such as those for birth control, must be removed after they release their contents. The 3-D printing process is being used to make implantable devices that are biodegradable in the body, Dr. Rowe added.
Many pharmaceuticals now on the market have known profiles for when they are most effective in combating a particular malady. Dr. Rowe said drug designers can match those known profiles to create very effective drugs using 3-D printing. The printing technology also can be used to put multiple "cocktail" drugs for a given illness into the same tablet--for example, a drug for chemotherapy and a drug to curb its side effects, said Mr. Palazzolo.
Professor Cima said 3-D printing not only promises more effective drugs, but also helps cut the costs of drug design. Pharmaceutical chemists must conduct exhaustive tests to determine the best formulation of drugs they develop. With current pill manufacturing technology, pharmaceutical companies must make large numbers of pills that each have the same dose. Testing slightly different formulations becomes a lengthy and expensive task. However, with 3-D printing, each pill in a bed can be made with a different formulation, so there is less waste and it takes less time to perform formulation studies, Professor Cima said.
"From a manufacturer's point of view, this is an advantage, because the cost to develop a drug is enormous," Professor Cima said. "The 3-D printing allows them to make different formulations rapidly and test them for efficacy."
Therics still needs to submit the 3-D printing process for approval by the FDA, which is a separate process from FDA approval of the drugs themselves. When that approval comes, Professor Cima said it will be possible to make prescription drugs by merely typing information concerning each patient into a computer and getting made-to-order pharmaceuticals from the drug manufacturer.
The scientists now plan to conduct basic research on how the manufacturing process will work (for example, how far the drug "bleeds" when it is deposited onto the powdered layers). They believe they may be better able to control drug doses and drug release by depositing the drugs in different regions of the pill or by using different powders.
Currently the process is limited to drugs requiring low dosages such as a few milligrams, because the drug is deposited as a solution. Other methods such as mixing the solid form of the drug with the matrix powder and enhancing the drug's solubility are being investigated to overcome these limitations.
Other MIT researchers are applying 3-D printing technology in other areas. For example, Linda G. Griffith, Karl Van Tassel Associate Professor of Chemical Engineering, and colleagues including Dr. Wu, are using this technology to construct bioerodible scaffolds for tissue-engineering studies.
A version of this article appeared in MIT Tech Talk on April 16, 1997.
