For children who need to take medicines, swallowing pills or tablets can be difficult. Researchers at the Massachusetts Institute of Technology (MIT) and Brigham and Women’s Hospital have developed a drug-delivering gel that is much easier to swallow and could be used to administer a wide range of drugs, not just to children, but to anyone who struggles to swallow solid pills.
The gels are made from plant-based oils, such as sesame oil, which are already used in the food industry, and can be prepared to exhibit different consistencies, from that of a thickened beverage to something more like a pudding, or a yogurt-like consistency. The gels are also stable without refrigeration, which could make them easier to transport to children in developing nations where there may be high rates of infant and child mortality.
Animal studies by the team showed that the gels can deliver several types of drugs for the treatment of infectious disease, in the same doses that can be delivered by pills or tablets. It’s hoped that a clinical trial could start within a few months.
“This platform will change our capacity for what we can do for kids, and also for adults who have difficulty receiving medication,” said Giovanni Traverso, PhD, the Karl van Tassel career development assistant professor of mechanical engineering at MIT and a gastroenterologist at Brigham and Women’s Hospital. “Given the simplicity of the system and its low cost, it could have a tremendous impact on making it easier for patients to take medications.”
Former MIT postdoc Ameya Kirtane, PhD, now an instructor at Brigham and Women’s Hospital, together with MIT postdoc Christina Karavasili, PhD, and former technical associate Aniket Wahane, PhD, are the lead authors of the team’s study, which is published in Science Advances, and titled, “Development of oil-based gels as versatile drug delivery systems for pediatric applications.”
Giving medication to children poses unique challenges, especially in resource-limited settings, the authors noted. “Administering medicines to 0- to 5-year-old children in a resource-limited environment requires dosage forms that circumvent swallowing solids, avoid on-field reconstitution, and are thermostable, cheap, versatile, and taste masking.”
Many drugs are formulated solids and provided as tablets that are not easily swallowed by children and which are also difficult to dose according to a child’s weight. While liquid and semi-solid alternatives exist for some drugs, many medications lack this option, or become unstable if there isn’t a reliable cold supply chain.
With drugs that are only available as pills, health care providers may try to dissolve them in water for children to drink, but that also requires a clean water supply, and the dosages may be difficult to get right if the pills are meant for adults. Some antibiotics and other drugs can be suspended in water, but that requires clean water to be available, and the drugs need to be refrigerated after being mixed. Also, this strategy doesn’t work for drugs that are not soluble in water.
Nearly 10 years ago, while working on other kinds of ingestible drug-delivery systems, the research team started to think about ways to make it easier for children to take medications that are normally given as pills. They set out to develop a new drug delivery system that would be inexpensive, palatable, stable at extreme temperatures, and compatible with many different drugs. They also wanted to make sure that drugs would not need to be mixed with water before dosing, and that the system could be used to deliver drugs either orally or as a suppository. “In this project, our goal was to develop a dosage form that could be used to administer medicines to children, especially in resource-limited settings,” they wrote.
Because the researchers wanted their formulation to work with drugs that can’t be dissolved in water, the researchers decided to focus on oil-based gels. Such gels, also known as oleogels, are commonly used in the food industry to change the texture of oily foods, and also to raise the melting point of chocolate and ice cream. In fact, the choice of oleogels as candidate drug carriers was “motivated by four factors,” the scientists stated. First, oils are excellent solvents for hydrophobic drugs, and “most drugs are hydrophobic,” they wrote. Second, the oils have an established safety profile. Third, manufacturing oleogels is simple and scalable, and lastly, oleogels are amenable to both oral and rectal administration, so they can be used used in newborns and infants, as well as children.
The researchers explored several types of plant-derived oils, including sesame oil, cottonseed oil, and flaxseed oil. They combined the oils with edible gelling agents such as beeswax and rice bran wax, and found that they could achieve different textures depending on the concentration and type of oil and gelling agent. “Oleogels were composed of three inactive ingredients, namely, gelling agents, solubilizers, and oils,” they explained. Some gels end up with a texture similar to that of a thick beverage, like a protein shake, while others are more like yogurt or pudding.
“Most liquid or semi-solid systems are water-based and pose limitations for delivering drugs that cannot be dissolved in water,” said Kirtane. “Our system is an oil-based system gel, which makes it compatible with most drugs. This enables the formulation of drugs that were not available in semi-solid or liquid dosage forms and allows patients, especially children, to more easily take their medicine … That approach gave us the capacity to deliver very hydrophobic drugs that cannot be delivered through water-based systems. It also allowed us to make these formulations with a really wide range of textures.”
The oleogels were also designed to stay stable at 40º C for several weeks, and even at up to 60º C for one week. While such high temperatures are uncommon, they might be reached when drugs are being transported by trucks without refrigeration.
To identify the gels that were the most palatable the researchers partnered with Sensory Spectrum, a consulting firm that specializes in consumer sensory experiences. Working with the company’s panels of professionally trained tasters, the researchers found that the most appealing gels included those made from oils that had a neutral flavor (such as cottonseed oil) or a slightly nutty flavor (like sesame oil). They also tailored the packaging of the oleogels to accommodate metered doses.
The researchers carried out a preclinical proof-of-concept study in pigs to evaluate the ability of the resulting gels to deliver three different water-insoluble drugs drawn from the World Health Organization’s list of essential medicines for children. The drugs included praziquantel, used to treat parasitic infections; lumefantrine, used to treat malaria; and azithromycin, used to treat bacterial infections. “Based on that list, infectious diseases really stood out in terms of what a country needs to protect its children,” Kirtane said. “A lot of the work that we did in this study was focused on infectious disease medications, but from a formulation standpoint, it doesn’t matter what drug we put into these systems.”
The tests demonstrated that for each drug the oleogels were able to deliver doses equal to or higher than the amounts that can be absorbed from tablets. The studies also confirmed that the water-soluble antibiotic, moxifloxacin hydrochloride, could be successfully delivered by a slightly modified oleogel, called an oleopaste. “A notable finding of this report is that oleogels and oleopastes may perform similarly to or better than commercial tablets,” the investigators stated. “We show that this system is highly versatile and can be used for the delivery of a variety of drugs.”
To store and deliver the drugs, the researchers designed a dispenser similar to a squeezable yogurt package, with compartments that can be used to separate doses. This could make it easier to deliver the right dosage for an individual child, depending on their weight. The team emphasized that the oleogel system could also be used for applications other than pediatric care in resource-limited settings. “We anticipate that this platform could be adopted for pediatric dosing, palliative care, and gastrointestinal disease applications,” they wrote.
“We have a very simple but very elegant solution to administering medications for those with swallowing difficulties,” said corresponding author Traverso. “This was an enormous team effort, which included fundamental formulation science, sensory evaluation and dispensing system fabrication and testing, and it was inspired by methods that are recognized and used already within the food industry.”
The authors concluded in their report, “In summary, we describe here gels made from food-based oils with highly malleable physicochemical properties that can be used for delivering drugs to children. We show the basic properties of this drug delivery platform designed for a highly vulnerable patient population and believe that these formulations will be an important tool toward improving overall health and well-being in children.”
The researchers have obtained FDA approval to carry out a Phase I clinical trial of their oleogel formulation of azithromycin, which they hope to start within the next few months at the Brigham and Women’s Hospital Center for Clinical Investigation.