3D printing pills: solved a big problem in medicine

In March 2017, 13-year-old Joseph was diagnosed with juvenile arthritis. Since then, he has been receiving treatment at Alder Hey Children's Hospital in Liverpool.

"He is very sick," Joseph's mother, Helen, told me. "He needs steroids, which is unavoidable, but one of the side effects of long-term use of steroids is that your body stops producing its own cortisol."

In fact, his adrenal gland has entered a dormant state.

To supplement the lost cortisol, he needs to take a hormone that is involved in the metabolism and immune system.

Joseph began taking hydrocortisone tablets in January 2018, and he continued to take it until his adrenal glands began to secrete cortisol again.

However, hydrocortisone is one of many drugs that cause problems for children.

In the UK, it is made into 10 mg or 20 mg per tablet, 10 mg dose, and adults usually take two to three tablets a day.

The instructions in the patient information booklet indicate that children should take “0.4 to 0.8 mg per day, taken two to three times”.

Therefore, it is the responsibility of the parents to cut each piece of 10 mg of tablets into pieces of several millimeters in size. Joseph ate half a slice every morning, half at noon, and a quarter at afternoon.

"I have no opinion on taking these pills," said Joseph, 15, now. "But having to chop them up is very annoying."

"It’s definitely a painful thing to have afternoon tea," Helen added.

"Because the afternoon tea time is not used to cut things. They did give us a small cutter, but it is really not easy to cut the tablets into a quarter size. It is easy to chop. The dose is often not accurate."

“This could be a serious problem,” explains Matthew Peak, research director at Alder Hey. “If they don’t take enough doses, they will fall asleep at school in the afternoon.”

"This may also oxidize. In the process of dividing the tablet, the active drug may cause an adverse reaction. Various problems may occur."

A few years ago, Pique began to consider whether it was possible to provide customized tablets for children and young people like Joseph.

The tablets are the size of them and contain the exact dose they need. He now believes this is possible, and the answer may lie in 3D printing.

On the way to Alder Hey, the taxi driver told me that his 11-year-old daughter was receiving diabetes treatment there. When he talked about the care of his child's "excellence" in this place, he had a big smile on his face.

This is a child-centered hospital: the overall design is inspired by the winners of the painting competition, and the children are involved in the entire design process.

Similarly, every child should have the opportunity to participate in clinical research, which is a core belief.

In 2017-2018, more than 9,000 children and young people participated in clinical research here.

3D printing pills: solved a big problem in medicine

The nine-year-old Ollie is one of the children who participated in the study.

“I want to participate in a study that will make it easier for poor children to take pills,” he said. “I have to swallow three pills and tell them if it is difficult to take.”

In the next study, he started experimenting with 3D printed tablets: "It's easy! All the pills are easy to swallow. If I am not good, I am happy to take it every day."

Ollie's father, Tim, is a research nurse at Alder Hey.

Based on his 15 years of experience, he suggested that his son be involved. “I have seen a lot of challenging situations with pills or liquid medications,” he told me.

He believes that the concept of letting children print drugs according to their choice of size, shape and even taste will be "beautiful" and will really help the child take the drugs prescribed by the doctor.

Usually, children often have difficulty swallowing pills or hate the taste of drugs.

There is still a long way to go for the future of babies and children, they need good medicine so they don't refuse to take it.

They need comfortable treatment so they don't resist and fear.

They need drugs that are appropriate for their age so that doctors can prescribe prescriptions accurately without having to cut or dilute the solid drug.

For the next two years, the team's goal is to take 3D printed tablets containing active drugs to children in need.

These pills will contain a precise dose of the anti-disease active drug, the size and shape (even color or taste) selected by young patients.

The first drug they tried would be hydrocortisone tablets, the kind of drugs that Joseph's family and many others are currently trying to use.

3D printing technology has been used to make chocolate, artificial coral, clothing, cars, and even homes. In the industrial sector, its main uses are rapid prototyping, manufacturing proof-of-concept models and creating products.

Medical applications include personalized prosthetics, dental implants, plastic and metal printed hand rests, and precise patient organ models to help surgeons plan complex surgeries.

However, 3D printing is also expected to be used to produce tablets of custom size and dosage.

The first and only 3D printing drug is Spritam, produced by Aprecia Pharmaceuticals.

Spritam is made with a 3D printer that combines some off-the-shelf parts with Aprecia's own technology.

In 2015, Spritam was approved by the US Food and Drug Administration to control seizures.

The printer prints a thin layer of powdered drug that binds the layers together at a microscopic level.

It squeezes more active ingredients than traditional manufacturing processes.

Traditional manufacturing processes compress drugs and other ingredients by stamping the formulation into a mold using a machine called a tablet press.

Despite the harshness of 3D printing products, the benefit of Spritam is that its porous layer structure dissolves quickly on the tongue.

This makes it easier for patients to take high doses of 1000 mg of active drug (levacetam) during seizures.

Not all drugs are suitable for this type of delivery, but there are other ways to help patients with 3D printed drugs.

3D printing pills: solved a big problem in medicine

Researchers at the University of London have found that the rate at which a drug is released in the body depends on the ratio of the surface area to the volume of the pill.

Pyramid-shaped pills release drugs faster than cubes or spheres.

They established a company, FabRx, in 2014 and plan to commercialize their “prints” in the next five to ten years.

Many pharmaceutical companies are also exploring the idea of ​​3D printing, although at least for quite some time, this technology seems unlikely to compete with traditional drug manufacturing methods.

The current technology allows GlaxoSmithKline to produce up to 1.6 million tablets per hour.

In contrast, Aprecia's 3D printers, even for large-scale production, can only produce tens of thousands of tablets per day.

This is not to say that 3D printing cannot continue to have an impact on the pharmaceutical industry. A major advantage is the ability to redistribute the production process and print medicines closer to the patient.

By decentralizing the production process, you can design a tablet in the UK and send it to California for printing.

If there is a printer, drugs can be printed in war and disaster areas, or in remote rural areas and low-income countries, without having to work hard to transport to difficult areas.

Even astronauts may benefit from 3D drug printing.

3D printed "polypills" can combine multiple drugs into a fixed-dose formulation, so each drug will have a unique release profile, some drugs will be released after ingestion, and others will take longer to dissolve and enter the patient's blood.

For those who need to take a variety of medications on a regular basis, such as the elderly and those who are treated for mental health problems, this approach may change their lives.

3D printing can also support the growing trend of personalized medicine, in which genomics-based drugs will only be available for specific patient populations.

In this case, 3D printing may be more efficient than traditional manufacturing.

Because the printer can be placed in a pharmacy, doctors and pharmacists can customize tablets, such as children, for those who benefit the most.

“We did a lot of lovely activities with the kids... We did some workshops and they wrote poems about drugs.”

Jenny Preston is the head of the Senior Patient and Public Involvement at the University of Liverpool. Her work at Alder Hey includes managing children and their families to participate in research in clinical research institutions.

She is also responsible for coordinating the work of the UK Youth Advisory Group, which allows children and young people aged 8-19 to express their opinions on the health research of people of their age.

In recent years, there has been an increasing emphasis on the importance of patient and public participation in drug research and design.

“The point is to make sure that young people and families have a say in everything we design,” she explains. “As a researcher, we are really interested, for example, to hear what young people think about age-appropriate formulas. It is crucial to look at young people’s perspectives right from the start.”

One of the ideas came from Robyn, who used to be a patient at Alder Hey and is still involved in the hospital's youth counseling group.

Eight years ago, when she was only 16 years old, she was diagnosed with polycystic ovary syndrome. This is the first time she has suffered from a disease and has experienced various pains that she is unable to take care of herself.

Sometimes, her treatment is going to stay in the clinic for a whole day.

When she was finally diagnosed, Robin realized that she had no drugs for young people that she had prepared for her.

“I have been taking drugs for eight years,” she said. "Of course, I prefer smaller, better-tasting pills. Sometimes you want to get sick afterwards."

“The idea of ​​producing drugs based on personal preferences is really exciting,” she added. “This technology allows children to control their condition. Many diseases take control of this disease, which can be terrible for children and their families.”

Beth Gibson agrees with this view.

She is a doctoral student working with the 3D drug program to develop a tool to assess children's acceptance of drugs.

She uses participatory techniques such as painting and discussion to explore young people's perspectives.

“A child said that she drew a colorful medicine because it reminded her of the sunset. She said it was like waking up every day to drink this fruit drink.”

Even if these children never get the fruits or chocolate medicines they dream of, Gibson's work shows that any level of input has the ability to change the child's attitude towards their condition.

“They didn’t have the right to choose drugs, and no one asked if they needed pills, capsules or liquids,” she said. “They said that even simple things are asked about what medicine they prefer, and they will have an impact on them.”

Previously published studies have shown that children, parents, and adult patients pay more attention to and benefit from active participation in their treatment, such as the formal process of understanding, monitoring, and reporting adverse drug reactions.

Other studies have found that joint decision-making in treatment plans often allows patients to have a better understanding of their condition and improve their emotional state.

Preston has organized a workshop with the consulting team and showed them how the 3D printer works.

Although the machine looks like a heavy black microwave oven, it seems to have its own life, projecting a purple glow on the newly emerging pills.

She told me that they all thought it was amazing.

“I think they feel that they are really important because they actually contribute to something quite big,” she said. "They may not be able to understand the big picture, but they understand that they are part of something very unique."

Between 2015 and 2018, the Alder Hey team collaborated with Mohamed Albed Alhnan, a pharmacist and 3D printing drug specialist at the University of Central Lancashire, who moved to King's College London in 2018.

Arnan and his colleagues focused on a 3D printing technology called fused deposition molding (FDM) and developed a system that uses chemical compounds and other common ingredients in drugs (such as Vegetable oil and paraffin) replace raw filaments or "ink" in FDM printers.

Even if the right "ink" has been created to carry the drug, and the 3D printer is also suitable for this task.

There are more different technical barriers for each drug.

FDM printers operate at temperatures around 100 degrees Celsius, which can affect components with poor thermal stability or alter the solubility of the drug.

3D Printing Pills: Solving a big medical problem "We are trying to build a platform to handle 90% of cases," Arnan said. "Of course, sometimes the structure of the drug will be affected or unstable, and you have to change the formula."

The Alder Hey team continues to work with scientists at the University of Central Lancashire, but they must make some changes to the 3D printer before they start printing drugs at a licensed pharmaceutical manufacturing facility.

“We will have to do some hard work to redesign some parts,” Pique said. “Pills produced by modified printers will undergo the same standard tests to check the quality assurance of the products. We expect these tablets to be identical or better than traditional tablets.”

Effective quality control is critical to driving a broader, more mainstream application of 3D printed pills, but there is no clear regulatory guidance.