Researchers affiliated with the University of Campinas in Brazil have developed an injectable formula to enhance the efficacy and prolong the duration of naproxen, which is used to treat temporomandibular joint (TMJ) inflammation. The injection involves lipid nanoparticles that have a high concentration of the active principle, which is gradually released into the TMJ to sustain the desired effect for up to 10 days without the need for repeated administration of the drug.
The use of the lipid nanoparticles enabled 99.8% of the naproxen to be encapsulated. The results of animal experiments showed that sustained delivery of the drug to the TMJ significantly reduced the migration of leukocytes to the joint for up to a week and induced low levels of the proinflammatory cytokines IL-1β and TNF-α, which are immune response regulators. These results indicated minimization of the inflammation.
“The enhanced efficacy of the drug in the inflamed joint was due above all to two strategies: gradual release of naproxen by the lipid nanocapsules into the affected region, and administration by injection,” rather than orally, said Eneida de Paula, last author of the article and a professor at the university’s Institute of Biology.
“These two factors prolonged the action of the anti-inflammatory drug without undesirable side effects, such as skin rash or stomach bleeding. Moreover, these results were observed in a joint that is not always effectively treated with this drug,” said de Paula.
Although the model used in the study was TMJ inflammation, a condition that affects some 10% of the world population, the development has potential applications in treating inflammation in other joints, the researchers said.
The inflammatory process associated with TMJ disorder results in the release of several pro-inflammatory cytokines and other immune signalers, all of which contribute to joint remodeling, cartilage degradation, and maintenance of a painful condition in the affected region. While nonsteroidal anti-inflammatory drugs (NSAIDs) such as naproxen are often prescribed for TMJ disorder, their efficacy is usually short-lived and last up to two days, the researchers said, and frequent re-administration is typically required.
“With the new injectable formulation, the anti-inflammatory effect lasts longer, and there are no side effects. The anti-inflammatory drug can be aggressive and cause ulcerations,” said de Paula. “Another problem is what’s known as first-passage metabolism, where the ingested drug is first metabolized by the liver, preventing the entire dose from entering the bloodstream and weakening the action of the drug.”
Intra-articular injection is more efficient when administering medications to treat disorders in the TMJ and other joints, the researchers said. But there are also many disadvantages, they added, such as the need for repeat administrations, which tend to be painful and decrease patient compliance.
“Injection into a joint is too painful to be repeated frequently, so we developed a formulation in which the drug is encapsulated and released slowly. This administration strategy and the prolonged effect eliminate the need for reinjections,” said de Paula.
The researchers designed the new formulation using factorial planning with the aid of computer software and mathematical models that enabled rational selection of the formulation with optimal deliverability and stability in terms of physicochemical and structural properties.
“The key was choosing the right combination of ingredients to make lipid nanoparticles suited to the drug, considering their biocompatibility and capacity to blend with naproxen,” said de Paula. “We already knew we should work with lipid nanoparticles because naproxen is hydrophobic, but instead of testing all possible combinations, we deployed a strategy known as factorial planning, whereby we identified the best variables and selected the ideal composition.”
The study, conducted in partnership with researchers at the university’s Institute of Chemistry, including the creation of a data matrix.
“The first tests were empirical. Their aim was to help us conform whether we could formulate a nanoparticle that would release the drug gradually inside the joint. Next, factorial planning enabled us to test a large number of combinations of ingredients and rationalize the search for the ideal formulation,” de Paula explained.
The new formulation completely encapsulates naproxen, delivers the medication in a controlled manner, and remains stable for a year when stored at 25°C. Factorial planning has been widely used to develop new drugs and is recommended by the United States Food and Drug Administration.
“Drug development is much faster and efficient when this strategy is used, as it lets you analyze different variables simultaneously. We’re now looking for a company with which to partner for the purpose of conducting clinical trials, after which the method can be commercialized,” said de Paula.
The study, “Improved Efficacy of Naproxen-Loaded NLC for Temporomandibular Joint Administration,” was published by Scientific Reports.