Thanks to a new injectable formulation, Brazilian researchers have been able to increase the effectiveness and duration of a drug commonly used to treat joint inflammation. The innovation involves lipid nanoparticles containing a high concentration of the active ingredient, which is gradually released into the affected joint while maintaining the desired effect for up to 10 days, with no need for reapplications.

In an article published in the journal Scientific Reports, scientists from the State University of Campinas (UNICAMP) describes tests of the new administration methodology made with the anti-inflammatory naproxen in rats with inflammation in the temporomandibular joint (TMJ) —responsible for actions such as opening the mouth and chewing food.

Results from the in vivo experiment showed that sustained delivery of the drug to the TMJ significantly decreased for one week migration to the site of defence cells (leukocytes) and immune response signaling levels such as pro-inflammatory interleukin cytokines 1 (IL-1β) and tumor necrosis factor alpha (TNF-α). These are signs that the inflammation has been softened.

The greater efficiency of the drug in the inflamed joint is mainly due to two strategies: the fact that the lipid nanocapsules gradually release naproxen in the affected region and the injectable [non-oral] administration of the drug. We were able to insert 99.8% of naproxen into lipid nanocapsules,” said Eneida de Paula, a professor at the UNICAMP Institute of Biology and author of the article.

According to the researcher, these two factors made the anti-inflammatory action last longer, without undesirable side effects, such as irritations and stomach ulcers, for example.

Although the study was conducted on models of acute TMJ inflammation —a problem that affects 10% of the world’s population— the innovation has potential application in the treatment of inflammation in other joints.

In the right place

The inflammatory process associated with TMJ dysfunction results in the release of a series of proinflammatory cytokines and other immune signals that contribute to cartilage degradation, joint remodeling and pain in the affected region.

Although the use of non-steroidal anti-inflammatory drugs, such as naproxen, is commonly prescribed for the treatment of these disorders, their effect usually lasts for a short-term (up to two days of relief), creating the need for re-administration.

With the new injectable formulation, the anti-inflammatory effect lasts longer and there are no side effects. This type of medicine can harm the stomach and cause ulcerations. Another problem is the so-called first-pass metabolism, which occurs when the oral drug is first metabolized by the liver, reducing the therapeutic action at the affected site,” said de Paula.

In this sense, intra-articular injection is more efficient for the administration of medications to treat TMJ and other joints. However, there are also disadvantages, such as the need to repeat doses, which decreases patient compliance with treatment.

Injection into a joint is too painful to repeat, so we made a formulation that would encapsulate the drug and gradually release it. This drug delivery system and its consequent prolonged effect eliminated the need for reinjections,” he said.

The right choice

To develop the new formulation, the researchers used factorial design strategies. With the aid of software and mathematical models, it was possible to rationally select the formulation that provided the ideal and stable delivery system (in terms of its physicochemical and structural properties).

Our secret was to choose a good combination of ingredients to make the lipid nanoparticles appropriate for the drug, considering its biocompatibility and ability to mix with naproxen. We already knew that we should work with lipid nanoparticles, as naproxen is hydrophobic [does not absorb water]. But instead of testing all possible combinations, we use a strategy known as factorial design. We first checked which were the best variables and selected the ideal compositions,” said de Paula.

From the study, done in collaboration with researchers from the UNICAMP Chemistry Institute, it was possible to create a data matrix. “The first tests were empirical, to decide if it was possible to formulate what we wanted: a nanoparticle that gradually released the drug into the joint. Then the factorial design allowed us to test a large number of ingredient combinations, streamlining the search for the ideal formulation,” he said.

In addition to being able to encapsulate virtually all naproxen and deliver the drug in a controlled manner, the new formulation remains stable for one year when stored at 25 °C.

The factorial design strategy has been employed for the development of new drugs and is recommended by the Food and Drug Administration (FDA). “Pharmaceutical development gets much faster and more efficient because you can analyze different variables at once. Now we are looking to partner with a company to conduct clinical trials and thus try to bring it to the market,” he said.


Source: Pfarma