3D printing technology enters the medical field, reshaping the “soul” of drugs in three-dimensional space

3D Printing teeth, 3D printing bones and joints, 3D printing heart models… Since 3D printing technology entered the medical field, this technology has brought many surprises to human beings. In the near future, 3D printing drugs may also come into our lives. Recently, Nanjing Sandieji Pharmaceutical Technology Co., Ltd.’s first 3D printed drug product, T19, has been approved by the US FDA for New Drug Clinical Trial (IND). Many researchers pointed out that compared with traditional pharmaceutical technology, 3D printing of drugs can provide new ideas for precise drug release, drug dosage control, improved R&D efficiency, and flexible pharmaceuticals through three-dimensional design.

Targeted release of drugs in three-dimensional space. 3D printing, also known as “additive manufacturing”, is a process of constructing and forming shapes by layering and depositing materials through specific digital design. In 1986, Professor Charles Hull of the University of California invented the first 3D. printer. Since the 1990s, many research institutions have begun to study how to create sparks with 3D printing technology in the field of pharmaceutical preparations. However, this progress is still in its infancy compared to 3D printing applications in aerospace, automobile manufacturing, construction, jewelry and other fields. But if you never forget, there must be an echo. In July 2015, the world’s first anti-epileptic drug SPRITAM (levetiracetam) instant tablet developed by Aprecia Pharmaceuticals of the United States was approved by the U.S. Food and Drug Administration (FDA) for marketing. The medicine is made of layers with many pores inside, which can be quickly dissolved by saliva in the mouth. The listing of Levetiracetam soon caused a butterfly effect in China on the other side of the ocean. A week before Levetiracetam was approved for listing, the “Triassic” was born. Five years later, the 3D printing drug product developed by this company passed the FDA new drug clinical trial application. “T19 is a drug designed for rheumatoid arthritis. Our goal is that patients take T19 before going to bed, and the concentration of the drug in the blood reaches the peak in the morning when the symptoms of pain, joint stiffness, and dysfunction are the most severe. Maintain the blood drug concentration during the day to achieve the best drug treatment effect.” Dr. Yu Zheng, manager of the Triassic Innovation Center, told the Science and Technology Daily reporter that this requires designing the three-dimensional structure of the tablet to allow the drug to be accurately released at a specific time. How to make the drug “smart” exert its effect at the right time depends on the initial release time and release rate of the drug. “The initial release time can be controlled by adjusting the thickness of the erodible material coated on the drug core, and the drug release rate can be adjusted by changing the geometry and exposed area of ​​the drug core. Such as hypertension, arthritis, etc. When the symptoms are the most severe in the morning, we control the structure of the tablet so that the peak time after the release of the drug coincides with the peak onset. In addition, through the design of multiple independent chambers in a tablet, we can Different drug release methods can be combined flexibly, and compound prescriptions can also be realized.” Zheng Yu said that different structural designs can allow drugs to take effect quickly and continue to work, improve drug efficacy or reduce side effects, and make it more convenient for patients to take drugs. For example, a medicine that was originally taken 3 times a day may be reduced to once a day.

Provide new ideas for precise design of drug dosage form structure, precise drug release, and improvement of R&D efficiency. Packaging various drug ingredients that are invisible to the naked eye into “listening” wherever the wizard refers, the “designer” behind the scenes is 3D printing technology . “Hot melt extrusion deposition” (hereinafter referred to as MED) is the core of the Triassic 3D printing technology. “Simply put, it is to mix powdered raw materials and polymer adjuvants and soften or melt them into a flowable semi-solid. Through accurate control of temperature and pressure, it can be extruded with high precision from the nozzle to become an accurate quantitative The three-dimensional movement of the printing platform is controlled by the computer to form a pre-designed medicine with an internal three-dimensional structure. The computer controls the three-dimensional movement of the printing platform to form a pre-designed medicine with an internal three-dimensional structure.” Zheng Yu said that the MED printer contains multiple printing stations, each A printing station is responsible for printing a component of the tablet structure, and multi-material printing is realized through the cooperation of multiple printing stations, and a tablet with a specific internal structure is produced. “It takes an average of 2-6 minutes from feeding to printing and molding, and the daily production capacity can reach 30,000 pieces. Each printing station can contain multiple print heads. At present, we have established a printing station with 32 print heads.” Zheng Yu said that they have also designed a data acquisition and monitoring control system that can monitor the size, structure, weight and uniformity of the drug in the entire process of raw material feeding, mixing, 3D printing and packaging, which is important for key processes. Parameters, intermediates and final products are monitored in real-time and production feedback control throughout the entire process to improve the quality of pharmaceutical products, reduce production costs, and facilitate regulatory supervision. This technology was accepted by the FDA’s Emerging Technology Group (ETT) last year. The simple and flexible production process also makes it possible to reduce the cost of research and development of new drugs. Zheng Yu said that for some pharmaceutical companies, large-cost investment often may not be able to obtain the desired drug candidates. And 3D printing technology can quickly develop small batches of prescriptions with different drug release mechanisms in the early stage of innovative drug research and development, which is helpful to explore the mechanism of action of innovative drugs and quickly screen out the most effective dosage form. “For example, based on the target release curve, we will select the appropriate dosage form structure and prescription ratio from the database, quickly print the prototype, and then compare the dissolution results with the target release curve to calibrate the dosage form and prescription. This changes the traditional Long-period trial-and-error formulation development methods greatly improve the efficiency and success rate of drug product development, and reduce development time and cost.” Zheng Yu said that currently international pharmaceutical giants such as Merck, AstraZeneca, and Merck are all trying Use 3D printing technology for new drug research and development. The new drug formulation structure and preparation method also bring opportunities to the protection of intellectual property rights of drugs. Zheng Yu said that before the patent protection of the original drug expires, 3D printing technology can be used to improve the preparation process, iterate new dosage forms, improve the efficacy of the drug product, reduce side effects, and thus extend the life cycle of the drug product. Enjoy market exclusivity.

Large-scale mass production is worth looking forward to. “Traditional pharmaceutical technology does not have good micro-precision control and spatial precision control capabilities. The distribution of drugs and excipients in the product is almost completely controlled by mixing or coating. It is difficult to design complex dosage forms. 3D printing The emergence of technology and the use of digital design have provided new ideas for the development of immediate-release preparations, improved preparations and compound preparations.” said Sun Minyi, PhD supervisor and professor at the School of Pharmacy, China Pharmaceutical University, the application of 3D printing in the pharmaceutical industry, Improve the flexibility of the industry’s processing procedures. “Traditional drug processing requires the powder to be made into granules and then compressed. This process involves many machines and production lines. A production line is often tens of thousands of yuan. Once a fixed process flow is formed, the cost of replacing the equipment is very high. But. 3D printing can replace modules and procedures. In principle, each medicine can be different.” Zheng Yu said that in the industrial production stage, because the printing principle is the same as that in the research and development stage, it is easier to control and can eliminate the need for traditional preparation technology to scale up production. Process, thus saving time and cost, single manufacturing equipment, reducing management cost. Other scholars expect that 3D printing of medicines is more convenient for the personalized design of medicines. For example, the current drug dosage is standardized, and some patients often need to rely on breaking the pills to obtain the required dosage. Therefore, the standardized dosage of the drug cannot meet the needs of all patients. In principle, 3D printing technology can change the dosage by modifying the size of the tablet or the filling percentage. The pharmacist can determine the most suitable dosage and form of administration for the patient according to the patient’s gender, age, race and other information, and then use the 3D printing technology Prepare relevant preparations. 3D printing technology is suitable for printing which drugs? In Zheng Yu’s view, “Those drugs that need to be controlled procedurally to achieve better curative effects, 3D printing has more room for realization.” In Sun Minyi’s view, individuality is needed. Chemical drug delivery and cost-insensitive drugs are more suitable for 3D printing. MED technology is only the tip of the iceberg of 3D printing drugs. At present, 3D printing technologies used in the pharmaceutical industry include adhesive injection technology and stereo light curing molding technology. However, due to the particularity of the preparation method, the fields of raw materials, process parameters, and intellectual property rights still face technical challenges. Sun Minjie told the reporter of Science and Technology Daily that in terms of materials, most of the 3D printing materials currently used in pharmaceutical preparations are polyvinyl alcohol, polyethylene, polypropylene, polycaprolactone, polyethylene glycol, etc., which have been approved by the FDA for clinical use. Materials, but this cannot fully meet the requirements of formulation design. It is necessary to modify materials or develop new materials to better achieve individualized requirements. “In addition, 3D printers with different technical principles have different requirements for materials. For example, fused deposition technology requires the use of thermoplastic polymer extrusion to manufacture products, while the printing materials of stereo light curing molding technology are only limited to photopolymers.” Say. The research and development of an original drug for the market requires a large cycle and large investment. In the era of 3D printing of drugs, how to ensure the intellectual property rights of the original research drugs is also the focus of Sun Ji’s concern. “After the patent protection period of the original research drug, the use of 3D printing drugs can quickly imitate the original research drug, but the current 3D printing technology patents are monopolized by large companies, and the endless 3D printing innovations will increase the protection of drug intellectual property rights? Difficult and complicated?” However, in Zheng Yu’s view, 3D printing drugs is one of the future development directions of the pharmaceutical industry. “From the perspective of the entire 3D printing drug industry, the 3D printing drug technology that can achieve large-scale mass production is still the most anticipated breakthrough. In recent years, multinational pharmaceutical companies such as Merck (Germany) and AstraZeneca have also begun to cooperate with 3D Printing equipment companies cooperate with universities to explore the feasibility of using 3D printing technology to prepare clinical trial drug samples and further commercial production.” “At present, it is impossible for 3D printing technology to completely replace traditional pharmaceutical technology in the short term. , But the application of 3D printing technology in the field of industrial pharmacy has effectively promoted the development of drug delivery systems, and will surely become an important thrust for future research.” Sun Minyi said.