Drug delivery oleogels could help the drug go down

For children who must take medication, 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 can be used to deliver a wide range of drugs, not just to children, but to anyone. person in difficulty. swallow solid pills.

The gels are made from vegetable oils, such as sesame oil, which are already used in the food industry, and can be prepared to have different consistencies, from that of a thickened drink to something resembling more like a pudding or yogurt. like consistency. The gels are also stable without refrigeration, which could make it easier to transport them to children in developing countries where infant and child mortality rates can be high.

Animal studies conducted by the team have shown that the gels can deliver several types of drugs for the treatment of infectious diseases, at the same doses that can be delivered by pills or tablets. It is hoped that a clinical trial will be able to start within a few months.

“This platform will change our ability to what we can do for children, as well as for adults who have difficulty receiving medication,” said Giovanni Traverso, PhD, Assistant Professor of Career Development Karl van Tassel in mechanical engineering at MIT and a gastroenterologist at Brigham. and the Women’s Hospital. “Given the simplicity of the system and its low cost, it could have a huge impact on making it easier for patients to take medication.”

Former MIT postdoctoral fellow Ameya Kirtane, PhD, now an instructor at Brigham and Women’s Hospital, along with MIT postdoctoral fellow Christina Karavasili, PhD, and former technical associate Aniket Wahane, PhD, are lead authors of the team’s study, which is published in Scientists progressand 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. “Delivering medication to children 0-5 years of age in a resource-limited setting requires dosage forms that avoid swallowing solids, avoid reconstitution in the field, and are heat-stable, inexpensive, versatile, and taste-masking. “

Many drugs are formulated in solid form and supplied as tablets which are not easily swallowed by children and are also difficult to dose based on the weight of the child. Although there are liquid and semi-solid alternatives for some drugs, many drugs do not have this option or become unstable if there is no reliable cold supply chain.

With medications that are only available in pill form, healthcare providers can try dissolving them in water for children to drink, but this also requires a clean water supply, and dosages can be difficult to obtain correctly if the pills are for adults. Some antibiotics and other drugs can be suspended in water, but this requires clean water to be available and the drugs must be refrigerated after mixing. Also, this strategy does not work for drugs that are not water soluble.

Almost 10 years ago, while working on other types of ingestible medication delivery systems, the research team began thinking about ways to make it easier for children to take normally administered medications. in the form of 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 ensure that the drugs would not need to be mixed with water before dosing and that the system could be used to deliver drugs orally or in suppository form. “In this project, our goal was to develop a dosage form that could be used to deliver medication to children, especially in resource-limited settings,” they wrote.

Because the researchers wanted their formulation to work with drugs that cannot be dissolved in water, the researchers decided to focus on oil-based gels. Such gels, also called oleogels, are commonly used in the food industry to modify the texture of fatty foods, as well as to raise the melting point of chocolate and ice cream. In fact, the choice of oleogels as drug carrier candidates was “driven by four factors”, the scientists said. First, oils are excellent solvents for hydrophobic drugs, and “most drugs are hydrophobic,” they wrote. Second, the oils have an established safety profile. Third, the manufacture of oleogels is simple and scalable, and finally, oleogels can be administered both orally and rectally, so that they can be used in newborns and infants, as well as in babies. children.

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 discovered that they could achieve different textures depending on the concentration and type of oil and gelling agent. . “The oleogels were composed of three inactive ingredients, namely gelling agents, solubilizers and oils,” they explained. Some gels end up having a texture similar to a thick drink, 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,” Kirtane said. “Our system is an oil-based gel system, which makes it compatible with most medications. This enables the formulation of drugs that were not previously available in semi-solid or liquid dosage forms and makes it easier for patients, especially children, to take their medications… This approach has given us the ability to deliver drugs very hydrophobic which cannot be delivered by water. based systems. It also allowed us to make these formulations with a very wide range of textures.

The oleogels have also been designed to remain stable at 40°C for several weeks, and even up to 60°C for a week. Although such high temperatures are rare, they can be reached when drugs are transported by trucks without refrigeration.

To identify the most palatable gels, the researchers teamed up with Sensory Spectrum, a consulting firm specializing in consumer sensory experiences. Working with the company’s panels of professional tasters, the researchers found that the most appealing gels included those made from neutral-flavored oils (like cottonseed oil) or slightly nutty flavored (like coconut oil). sesame). They also adapted the packaging of the oleogels to accommodate measured doses.

The researchers conducted a proof-of-concept preclinical study in pigs to assess the ability of the resulting gels to deliver three different water-insoluble drugs from the World Health Organization’s Essential Medicines List 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 this list, infectious diseases really stood out in terms of what a country needs to protect its children,” Kirtane said. “A lot of the work we did in this study was focused on infectious disease drugs, but from a formulation perspective, it doesn’t matter what drug we put in those systems.”

The tests showed that for each drug, the oleogels were able to deliver doses equal to or greater than the amounts that the tablets could absorb. The studies also confirmed that the water-soluble antibiotic, moxifloxacin hydrochloride, could be successfully delivered by a slightly modified oleogel called oleopaste. “A notable finding from this report is that oleogels and oleopastes may have similar or better performance than commercial tablets,” the investigators said. “We show that this system is very 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 wrapper, with compartments that could be used to separate doses. This could make it easier to administer the right dosage for an individual child, based on their weight. The team pointed out 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 yet very elegant solution for delivering medication to people with swallowing difficulties,” said corresponding author Traverso. “It was a huge team effort, which included the basic science of formulation, sensory evaluation and manufacturing and testing of dispensing systems, and it was inspired by methods that are already recognized and used in the industry. ‘food industry.”

The authors concluded in their report: “In summary, we describe here gels made from edible oils with highly malleable physicochemical properties that can be used to administer medication 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 to improve the health and well-being of children.

The researchers have obtained FDA approval to conduct 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.